CN102952157A - Intermediates for synthesis of benzindene prostaglandins and preparations thereof - Google Patents
Intermediates for synthesis of benzindene prostaglandins and preparations thereof Download PDFInfo
- Publication number
- CN102952157A CN102952157A CN2012103053798A CN201210305379A CN102952157A CN 102952157 A CN102952157 A CN 102952157A CN 2012103053798 A CN2012103053798 A CN 2012103053798A CN 201210305379 A CN201210305379 A CN 201210305379A CN 102952157 A CN102952157 A CN 102952157A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- group
- carry out
- make
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 benzindene prostaglandins Chemical class 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000000543 intermediate Substances 0.000 title abstract description 8
- 229940094443 oxytocics prostaglandins Drugs 0.000 title abstract description 5
- 230000015572 biosynthetic process Effects 0.000 title description 5
- 238000003786 synthesis reaction Methods 0.000 title description 5
- 238000000034 method Methods 0.000 claims abstract description 77
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical class O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 claims abstract description 48
- 150000001875 compounds Chemical class 0.000 claims description 172
- 239000002585 base Substances 0.000 claims description 138
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 88
- 239000002904 solvent Substances 0.000 claims description 45
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 229960005032 treprostinil Drugs 0.000 claims description 23
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 claims description 23
- 239000003153 chemical reaction reagent Substances 0.000 claims description 21
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 20
- 238000005984 hydrogenation reaction Methods 0.000 claims description 19
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 18
- 230000029936 alkylation Effects 0.000 claims description 17
- 238000005804 alkylation reaction Methods 0.000 claims description 17
- 238000005822 methylenation reaction Methods 0.000 claims description 16
- 239000003513 alkali Substances 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 14
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 claims description 10
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 229910000085 borane Inorganic materials 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 10
- 229910052796 boron Inorganic materials 0.000 claims description 9
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 9
- 230000006103 sulfonylation Effects 0.000 claims description 9
- 238000005694 sulfonylation reaction Methods 0.000 claims description 9
- 230000003647 oxidation Effects 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 7
- 239000002168 alkylating agent Substances 0.000 claims description 7
- 238000006197 hydroboration reaction Methods 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 125000000468 ketone group Chemical group 0.000 claims description 7
- MMOPHTBJNNBLFU-UHFFFAOYSA-N 1-(4-fluorophenyl)-3-piperidin-1-ylpropan-1-one Chemical compound C1=CC(F)=CC=C1C(=O)CCN1CCCCC1 MMOPHTBJNNBLFU-UHFFFAOYSA-N 0.000 claims description 6
- 229910000761 Aluminium amalgam Inorganic materials 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 230000020176 deacylation Effects 0.000 claims description 6
- 238000005947 deacylation reaction Methods 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- JFRNUTJWOFAIOT-UHFFFAOYSA-N CN=S(=O)(CN)C1=CC=CC=C1 Chemical compound CN=S(=O)(CN)C1=CC=CC=C1 JFRNUTJWOFAIOT-UHFFFAOYSA-N 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 4
- 239000011877 solvent mixture Substances 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 151
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 108
- HHSARRMUXPDGJD-UHFFFAOYSA-N butyl(dimethyl)silicon Chemical group CCCC[Si](C)C HHSARRMUXPDGJD-UHFFFAOYSA-N 0.000 description 72
- 239000000203 mixture Substances 0.000 description 56
- 235000019439 ethyl acetate Nutrition 0.000 description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000011541 reaction mixture Substances 0.000 description 48
- 239000012043 crude product Substances 0.000 description 37
- 238000010898 silica gel chromatography Methods 0.000 description 34
- 238000000746 purification Methods 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 238000001035 drying Methods 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 30
- 239000003795 chemical substances by application Substances 0.000 description 30
- 238000010828 elution Methods 0.000 description 30
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 27
- 239000000243 solution Substances 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 238000003810 ethyl acetate extraction Methods 0.000 description 25
- 239000007787 solid Substances 0.000 description 25
- 239000010410 layer Substances 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 23
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 22
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 22
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 22
- 229910052760 oxygen Inorganic materials 0.000 description 22
- 239000001301 oxygen Substances 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- 239000007864 aqueous solution Substances 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 0 CC1C2(CCCC2)C1CC** Chemical compound CC1C2(CCCC2)C1CC** 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 15
- 150000004702 methyl esters Chemical class 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 12
- 239000000376 reactant Substances 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 238000010790 dilution Methods 0.000 description 11
- 239000012895 dilution Substances 0.000 description 11
- 238000012545 processing Methods 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- SOKKGFZWZZLHEK-UHFFFAOYSA-N butoxy(dimethyl)silane Chemical group CCCCO[SiH](C)C SOKKGFZWZZLHEK-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 239000012266 salt solution Substances 0.000 description 7
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- 239000000908 ammonium hydroxide Substances 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 229940100198 alkylating agent Drugs 0.000 description 4
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 4
- QCIWZIYBBNEPKB-UHFFFAOYSA-N tert-butyl(dimethyl)silane Chemical compound C[SiH](C)C(C)(C)C QCIWZIYBBNEPKB-UHFFFAOYSA-N 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 4
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 3
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000012456 homogeneous solution Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- KWKAKUADMBZCLK-UHFFFAOYSA-N 1-octene Chemical compound CCCCCCC=C KWKAKUADMBZCLK-UHFFFAOYSA-N 0.000 description 2
- QRIZNMGCIBXULQ-UHFFFAOYSA-N 1h-cyclopenta[a]naphthalene-1-carbonitrile Chemical compound C1=CC=CC2=C3C(C#N)C=CC3=CC=C21 QRIZNMGCIBXULQ-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- SQUPBVCRSYNHPF-UHFFFAOYSA-N CCCCCC([O])CC Chemical compound CCCCCC([O])CC SQUPBVCRSYNHPF-UHFFFAOYSA-N 0.000 description 2
- LMHIPJMTZHDKEW-XQYLJSSYSA-M Epoprostenol sodium Chemical compound [Na+].O1\C(=C/CCCC([O-])=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 LMHIPJMTZHDKEW-XQYLJSSYSA-M 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 2
- 229910000105 potassium hydride Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 208000002815 pulmonary hypertension Diseases 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 125000005309 thioalkoxy group Chemical group 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- JLIDVCMBCGBIEY-UHFFFAOYSA-N 1-penten-3-one Chemical compound CCC(=O)C=C JLIDVCMBCGBIEY-UHFFFAOYSA-N 0.000 description 1
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical group CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- RFRQNYTYUJLZCJ-UHFFFAOYSA-N Cc1cc(OP)ccc1 Chemical compound Cc1cc(OP)ccc1 RFRQNYTYUJLZCJ-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 101000643895 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 6 Proteins 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 102100021015 Ubiquitin carboxyl-terminal hydrolase 6 Human genes 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- CHIHQLCVLOXUJW-UHFFFAOYSA-N benzoic anhydride Chemical compound C=1C=CC=CC=1C(=O)OC(=O)C1=CC=CC=C1 CHIHQLCVLOXUJW-UHFFFAOYSA-N 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- HXLVDKGPVGFXTH-UHFFFAOYSA-N butyl(dimethyl)silane Chemical group CCCC[SiH](C)C HXLVDKGPVGFXTH-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical class C1(=CCCC1)* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- UBHZUDXTHNMNLD-UHFFFAOYSA-N dimethylsilane Chemical compound C[SiH2]C UBHZUDXTHNMNLD-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940001440 flolan Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- KCXYZMFPZHYUFO-UHFFFAOYSA-N n-methyl-n-phosphanylmethanamine Chemical compound CN(C)P KCXYZMFPZHYUFO-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/11—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton
- C07C255/13—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
- C07C37/003—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain by hydrogenation of an unsaturated part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
- C07C37/0555—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group being esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/50—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions decreasing the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/283—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by hydrogenation of unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/017—Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/18—Acetic acid esters of trihydroxylic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/78—Benzoic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/14—Benz[f]indenes; Hydrogenated benz[f]indenes
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Catalysts (AREA)
Abstract
Novel processes for preparing optically active cyclopentanones 1 which are useful for the preparation of benzindene Prostaglandins and novel cyclopentanones are provided. The invention also provides novel processes of preparing benzindene prostaglandins and novel intermediates for benzindene prostaglandins.
Description
Technical field
The present invention relates to the novel method for the preparation of the cyclopentanone of formula 1,
Described cyclopentanone is applicable to prepare the benzindene prostaglandin(PG).The invention still further relates to the Novel ring pentanone by described method preparation.
Background technology
Flolan (prostaglin X (Epoprostenol)) is used for the treatment of the first medicine of pulmonary hypertension by Food and Drug Administration (Food and Drug Administration) approval.Yet prostaglin X is extremely unstable and usually have about 3 ~ 5 minutes transformation period, and need to offer medicine to give and store at a lower temperature by continuous intravenously.Benzindene prostaglandin(PG) (for example UT15 (treprostinil that (Treprostinil))) is the derivative of prostaglin X and is the medicine that a new class is used for the treatment of pulmonary hypertension.The benzindene prostaglandin(PG) is more stable and therefore more convenient and safer than prostaglin X in utilization.
As shown in Scheme 1, the cyclopentanone of formula 1a be for the synthesis of the important intermediate of benzindene prostaglandin(PG) (for example UT15) (tetrahedron communication (Tetrahedron Letters), (1982), 23 (20), 2067-70):
Flow process 1
Yet as shown in Scheme 2, the synthetic of the cyclopentanone of formula 1a should begin and experience eight steps (organic chemistry magazine (J.Org.Chem.) with intermediate B, the 43rd volume, o. 11th, 1978), and will be referred to 20 above chemical steps, comprise the step of synthetic intermediate B.This synthetic extremely complicated and only reach low yield.
Flow process 2
Therefore, need to relate to less step in the industry and operate more convenient cyclopentanone for the preparation of formula 1 and the method for benzindene prostaglandin(PG).
Summary of the invention
The invention provides novel method and the Novel ring pentanone of preparation optical activity cyclopentanone 1.
The present invention also provides the novel method of preparation benzindene prostaglandin(PG) and the novel intermediates of benzindene prostaglandin(PG).
Embodiment
I. definition
Term used herein " alkyl " refers to contain the straight or branched alkyl of 1 to 30 carbon atom, such as methyl, ethyl, sec.-propyl, the tertiary butyl etc.; Or have a cyclic saturated hydrocarbon base of 3 to 10 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, menthyl etc.
Term used herein " low alkyl group " refers to contain the straight or branched alkyl of 1 to 6 carbon atom, such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl etc.
Term used herein " aryl " refers to monocycle or Ppolynuclear aromatic alkyl, such as phenyl, naphthyl, anthryl, phenanthryl etc.Aryl optionally replaces through one or more substituting groups, and substituting group includes, but is not limited to halogen, alkoxyl group, thioalkoxy group, alkyl and aryl.
Term used herein " aralkyl " refers to contain the straight or branched hydrocarbon of 1 to 20 carbon atom and one or more aforesaid aryl, such as benzyl, diphenyl-methyl, fluorenyl methyl etc.
Abovementioned alkyl, aryl and aralkyl optionally replace through one or more substituting groups that are selected from by the following group that forms separately: halogen, alkyl, aryl, alkoxyl group, aryloxy, thioalkoxy group, the sulphur aryloxy, alkylamino, virtue is amino, cyano group, nitro, alkoxy carbonyl, aryl carbonyl, aromatic aminocarbonyl, alkyl amino-carbonyl, and carbonyl or be selected from by pyridyl, thienyl, furyl, imidazolyl, morpholinyl oxazolinyl, piperidyl, piperazinyl, THP trtrahydropyranyl, pyrrolidyl, the heterocyclic group of the group that pyrrolidone-base etc. form.
In the description that runs through the compound that this specification sheets provides, the overstriking taper
Expression substituting group (above planes of molecules or page) in the β direction, and be interrupted the torch line
Expression substituting group (below planes of molecules or page) in the α direction.
II. description of the invention
The cyclopentanone of formula 1
R wherein
2Be singly-bound or C
1-4Alkylidene group or formula-CH
2The group of O-; R
3Be C
1-7Alkyl or aryl or aralkyl, it is unsubstituted or separately through C
1-4Alkyl, halogen or trihalogenmethyl replace;
Be singly-bound or two key; P
1Be the protecting group of phenolic group, it preferably has acid acceptance and the alkyl that includes, but is not limited to be unsubstituted, allyl group, the benzyl that is unsubstituted or is substituted, ethanoyl, alkyl-carbonyl, methoxymethyl, methoxyl group thiomethyl, 2-methoxy ethoxy methyl, two (2-chloroethoxy) methyl, THP trtrahydropyranyl, tetrahydro thiapyran base, 4-methoxyl group THP trtrahydropyranyl, 4-methoxyl group tetrahydro thiapyran base, tetrahydrofuran base, tetrahydrochysene thio-furan base, 1-ethoxyethyl group, 1-methyl isophthalic acid-methoxy ethyl, trityl group or a SiR
aR
bR
c, R wherein
a, R
bAnd R
cBe C independently of one another
1-8Alkyl, phenyl, benzyl, the phenyl that is substituted or the benzyl that is substituted, and P
1The benzyl that more preferably is selected from allyl group, is unsubstituted or is substituted, ethanoyl, alkyl-carbonyl and SiR
aR
bR
c, R wherein
a, R
bAnd R
cBe C independently of one another
1-8Alkyl, phenyl, benzyl, the phenyl that is substituted or the benzyl that is substituted; P
2And P
3Identical or different and be the protecting group of hydroxyl, preferred tool alkaline stability and include, but is not limited to methoxymethyl, methoxyl group thiomethyl, 2-methoxy ethoxy methyl, two (2-chloroethoxy) methyl, THP trtrahydropyranyl, tetrahydro thiapyran base, 4-methoxyl group THP trtrahydropyranyl, 4-methoxyl group tetrahydro thiapyran base, tetrahydrofuran base, tetrahydrochysene thio-furan base, 1-ethoxyethyl group, 1-methyl isophthalic acid-methoxy ethyl, trityl group and SiR
aR
bR
c, R wherein
a, R
bAnd R
cBe C independently of one another
1-8Alkyl, phenyl, benzyl, the phenyl that is substituted or the benzyl that is substituted,
It is the ω side chain unit of enantiomer enrichment of cuprate of the alkynes of vinyl stannane by making halogenide derived from formula II-1, formula II-2 or formula II-3
Wherein X is halogen; R
4It is low alkyl group; And
R
2, R
3And P
3As hereinbefore defined, such as people such as old (Chen), 1978, organic chemistry magazine (J.Org.Chem.), 43,3450; USP4,233,231, USP4,415,501 and USP6, described in 294,679, all documents all are incorporated herein by reference; Optical activity cyclopentenone with formula III
P wherein
1And P
2As hereinbefore defined; In the suitable solvent that can be tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, isopropyl ether, methyl butyl ether, glycol dimethyl ether, toluene, heptane or hexane or its mixture and preferably carrying out coupled reaction under the temperature in-100 ℃ to 40 ℃ scopes prepares.
The optical activity cyclopentenone of formula III can prepare according to the method that discloses in the patent application case in the application that coexists of same date application and " for the preparation of the method for cyclopentenone with for the synthesis of the Novel ring pentenone (PROCESSES FOR PREPARING CYCLOPENTENONES AND NOVEL CYCLOPENTENONES FOR THE SYNTHESIS OF BENZINDENE PROSTAGLANDINS) of benzindene prostaglandin(PG) " by name.Subsequently, use such as the alkali cancellation such as ammonium hydroxide reactions, and stand the handling procedure that carries out in a usual manner.The gained crude product can utilize ordinary method (for example column chromatography or recrystallize) purifying, or not purified product can be directly used in next reaction.According to the present invention, the purifying of crude product 1 comprises the P that removes gained cyclopentanone 1
2And P
3Protecting group is removed impurity or the isomer that is produced by coupled reaction by crystallization, and again hydroxyl protection is obtained highly purified formula 1 cyclopentanone.
As shown in Scheme 3, formula 6 compounds (R wherein
2, R
3,
P
2And P
3By the preparation of formula 1 cyclopentanone as hereinbefore defined),
Flow process 3
As shown in the step (a) of flow process 3, the cyclopentanone of formula 1 stands wild fine jade-Lombardo reagent (Nozaki-Lombardo reagent) (Japanization association will (Bull.Chem.Soc.Jpn.), 53.1698 methylenation (1980)), form formula 2 compounds, described wild fine jade-Lombardo reagent is prepared by methylene bromide, zinc and titanium chloride (IV).Reaction can be carried out in any suitable solvent, for example is selected from the solvent of methylene dichloride, tetrahydrofuran (THF), ether, toluene or hexane or its mixture.Reaction is carried out under-50 ℃ to 100 ℃, preferred-20 ℃ of temperature in the room temperature range.The usage quantity of wild fine jade-Lombardo reagent so that reactant such as tlc (Thin Layer Chromatography, TLC) the monitoring complete reaction.After reaction is finished, can utilize such as remove excess reagent, extraction, dehydration, the handling procedure such as concentrated is isolated formula 2 compounds from reaction mixture.Can utilize column chromatography or utilize crystallization to be further purified product.
Can also pass through such as Johnson (Johnson), JACS (J.Am.Chem.Soc.), two step programs of 95,6462 (1973) institute's teachings are introduced methylene radical.For instance, the negatively charged ion of formula 1 cyclopentanone and aminomethyl phenyl-N-methyl-sulfoximine reacts in being fit to solvent, then in the solvent mixture of water-acetic acid-tetrahydrofuran (THF), process the thick adducts of gained, acquisition formula 2 compounds with aluminium amalgam (aluminium amalgam).
Can be by removing P
2And P
3Protecting group is to obtain corresponding formula 2 cyclopentanone (P wherein
2And P
3Through the H displacement), utilize crystallization to come corresponding formula 2 cyclopentanone of purifying to remove simultaneously impurity or the isomer of formula 2, and again hydroxyl protection is obtained highly purified formula 2 cyclopentanone with identical or different hydroxyl protecting group, come purifying formula 2 compounds.
As shown in the step (b) of flow process 3, formula 2 compounds are further converted to the alkylol cpd of formula 3.According to the present invention, then formula 2 compounds and borane reagent (for example 9-boron dicyclo [3,3,1] nonane (9-BBN)) reaction carries out oxidation with alkaline hydrogen peroxide, obtains the alkylol cpd of formula 3.
As shown in the step (c) of flow process 3, the alkylol cpd of formula 3 further stands sulfonylation with acquisition formula 4 compounds, wherein X
1Be alkyl sulphonyl, aryl sulfonyl or aralkyl alkylsulfonyl, for example methane sulfonyl or p-toluenesulfonyl.Sulfonylation is by using suitable alkylsulfonyl donor (for example methane sulfonyl chloride or Tosyl chloride) to realize under alkali (for example amine, for example triethylamine) exists.
As shown in the step (d) of flow process 3, formula 4 compounds stand deprotection reaction so that P
1Through the H displacement, or stand deprotection reaction and carry out hydrogenation together with the two keys to the ω side chain.The condition that is suitable for deprotection depends on variable P
1Work as P
1During for trialkylsilanyl, use fluorion (for example tetrabutyl ammonium fluoride) to realize deprotection reaction.Work as P
1During for the benzyl that is unsubstituted or is substituted, use hydrogenation catalyst and alkali/electrophilic reagent of being fit in being fit to solvent and in the presence of hydrogen, realize deprotection reaction.The hydrogenation catalyst that is fit to contain be selected from by palladium, platinum, rhodium and nickel with and the metal of the group of compositions of mixtures.The example of catalyzer comprises Pd-C, Pt-C and Ni.The solvent that is fit to can be selected from tetrahydrofuran (THF), ethyl acetate, methyl alcohol, ethanol or toluene or its mixture.For P wherein
1For the benzyl that is unsubstituted or is substituted and
Be formula 4 compounds of two keys, hydrogenation can obtain wherein
For formula 5 compounds of two keys finish, or can carry out continuously obtaining wherein
For formula 5 compounds of singly-bound, as being monitored by HPLC or TLC.
As shown in the step (e) of flow process 3, formula 5 compounds further stand alkylation in the molecule.Alkylation is to use the alkali that is fit to realize in the solvent that is fit in the molecule.The alkali that is fit to can be selected from sodium hydride, potassium hydride KH, lithium hydride, potassium tert.-butoxide or butyllithium or its mixture.The solvent that is fit to can be selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran, glyme or toluene or its mixture.Alkylation will produce the contraposition cyclisation isomer of a small amount of formula IV in the molecule.
Contraposition cyclisation isomer can be removed by column chromatography, or removes at the follow-up crystallisation step of the crystallization of intermediate that is used for acquisition benzindene prostaglandin(PG).
According to one embodiment of present invention, the invention provides a kind of method of preparation formula 6c compound,
P wherein
2, P
3, R
2And R
3As hereinbefore defined; Described method comprises following steps:
(1) makes the formula III compound
P wherein
1And P
2As hereinbefore defined; With the cuprate reaction derived from the compound of formula II-1a, formula II-2 or formula II-3,
Wherein X, R
2, R
3, R
4And P
3As hereinbefore defined; Form formula 1c compound
(2) make the ketone group of formula 1c compound carry out methylenation, form formula 2c methylene compound
(3) make formula 2c compound carry out hydroboration through borane reagent (for example 9-boron dicyclo [3,3,1] nonane), then carry out oxidation with alkaline hydrogen peroxide, obtain the alkylol cpd of formula 3c
(4) in the presence of alkali, make formula 3c compound carry out sulfonylation with alkylsulfonyl donor (for example methane sulfonyl chloride or Tosyl chloride), form formula 4c compound
X wherein
1Be alkylsulfonyl;
(5) remove P
1Group and make the two keys in the ω side chain carry out hydrogenation forms formula 5c compound
(6) make formula 5c compound carry out alkylation in the molecule, form formula 6c compound.
The methylenation of step (2) can undertaken by the wild fine jade-Lombardo reagent of methylene bromide, zinc and titanium chloride (IV) preparation is lower, or reacts in suitable solvent and then carry out with the thick adducts of aluminium amalgam processing gained in the solvent mixture of water-acetic acid-tetrahydrofuran (THF) by the negatively charged ion that makes formula 1c compound and aminomethyl phenyl-N-methyl-sulfoximine.
According to a preferred embodiment of the present invention, in formula 6c, R
2Be singly-bound and R
3Be amyl group.P
1Be the benzyl that is unsubstituted or is substituted, P
2And P
3Be the protecting group of hydroxyl independently, it preferably is selected from methoxymethyl, methoxyl group thiomethyl, 2-methoxy ethoxy methyl, two (2-chloroethoxy) methyl, THP trtrahydropyranyl, tetrahydro thiapyran base, 4-methoxyl group THP trtrahydropyranyl, 4-methoxyl group tetrahydro thiapyran base, tetrahydrofuran base, tetrahydrochysene thio-furan base, 1-ethoxyethyl group, 1-methyl isophthalic acid-methoxy ethyl, trityl group and SiR
aR
bR
c, R wherein
a, R
bAnd R
cBe C independently of one another
1-8Alkyl.
As shown in Scheme 4, UT-15 can be easily by the preparation of formula 6b compound, formula 6b compound is corresponding to wherein
Be singly-bound; R
2Be singly-bound; R
3Be amyl group; P
2And P
3Formula 6 compounds for the protecting group of hydroxyl.
Flow process 4
Method shown in the flow process 4 comprises:
(a) use alkylating agent XCH
2CN or XCH
2COOR
5(wherein X is halogen, for example Cl, Br or I; R
5Be alkyl) make the phenolic group of formula 6b compound carry out alkylation;
(b) with alkali make-CN or-COOR
5The group hydrolysis, formation-COOH group; With
(c) remove protecting group P
2And P
3
The step of above-mentioned preparation UT-15 can be carried out by any order, for example with (a) (b) (c) (b) or (c) (a) (b) order of (c), (a).Preferably, with (c) (a) (b) order carry out described method.
As shown in Scheme 5, UT-15 also can prepare from formula 6d compound, and formula 6d compound is corresponding to wherein
Be two keys; R
2Be singly-bound; R
3Be amyl group; P
2And P
3Formula 6 compounds for the protecting group of hydroxyl.
Flow process 5
Except above-mentioned steps (a), (b) with (c), described method comprises (d) comes hydrogenation of formula 6d compound with hydrogen in suitable solvent in the presence of hydrogenation catalyst and alkali/electrophilic reagent of being fit to two keys; Or wherein B, P
2' and P
3' be two keys of formula 9 compounds of H; Or wherein B is-CH
2COOR
5And P
2' and P
3' be two keys of formula 9 compounds of H or protecting group; Or wherein B is-CH
2COOH and P
2' and P
3' be two keys of formula 9 compounds of H or protecting group.
These steps can be carried out by any order, and for example (b) (c) (d) with (a), (a) (b) (d) (c), (d) (a) (b) (c), (a) (c) (b) (d), (a) (c) (d) (b), (a) (d) (c) (b), (d) (a) (c) (b), (c) (a) (b) (d), (c) (a) (d) (b) or (c) (d) (a) (b) order.For instance, an at first hydrogenation accepted way of doing sth of formula 6d compound 6b compound (namely carrying out step (d)) stands step (a), (b) and (c) with any order subsequently.Step preferably with (c) (d) (a) (b), (a) (c) (b) (d) or (a) (b) (c) order of (d) carry out.
According to an embodiment, the invention provides a kind of method for preparing treprostinil you (UT-15), described method comprises following steps:
(1) makes formula III a compound
P wherein
1Be allyl group, the benzyl that is unsubstituted or is substituted, ethanoyl, alkyl-carbonyl and SiR
aR
bR
c, R wherein
a, R
bAnd R
cBe C independently of one another
1-8Alkyl, phenyl, benzyl, the phenyl that is substituted or the benzyl that is substituted; And P
2As hereinbefore defined; With the cuprate reaction derived from the compound of formula II-1a, formula II-2 or formula II-3:
Wherein X, R
2, R
3, R
4And P
3As hereinbefore defined; Form formula 1d compound
(2) make the ketone group of formula 1d compound carry out methylenation, form formula 2d methylene compound
(3) make formula 2d compound carry out hydroboration with borane reagent (for example 9-boron dicyclo [3,3,1] nonane), then carry out oxidation with alkaline hydrogen peroxide, obtain the alkylol cpd of formula 3d
(4) in the presence of alkali, make formula 3d compound carry out sulfonylation with alkylsulfonyl donor (for example methane sulfonyl chloride or Tosyl chloride), form formula 4d compound
X wherein
1Be alkylsulfonyl;
(5) remove P
1Group forms formula 5d compound,
(6) make formula 5d compound carry out alkylation in the molecule, form formula 6d compound
(7) remove P
2And P
3Group forms formula 7d compound
(8) make the two keys in the ω side chain of formula 7d compound carry out hydrogenation, form formula 8d compound
(9) use alkylating agent XCH
2CN or XCH
2COOR
5(wherein X is halogen, for example Cl, Br or I; R
5Be alkyl) make phenolic group carry out alkylation, form formula 9d compound
Wherein Z be-CN or-COOR
5With
(10) with basic hydrolysis formula 9d compound-CN or-COOR
5Group forms the treprostinil that.
According to an embodiment, the invention provides a kind of method for preparing treprostinil you (UT-15), described method comprises the step of above-mentioned (1) ~ (6), forms formula 6d compound, subsequently
(7) use alkylating agent XCH
2CN or XCH
2COOR
5(wherein X is halogen, for example Cl, Br or I; R
5Be alkyl) make phenolic group carry out alkylation, form formula 7D compound
Wherein Z be-CN or-COOR
5And
(8) remove P
2And P
3Group forms formula 8D compound
(9) with basic hydrolysis formula 8D compound-CN or-COOR
5Group forms formula 9D
(10) make the two keys in the ω side chain of formula 9D compound carry out hydrogenation, form treprostinil you.
According to another embodiment, the invention provides a kind of alternative method for preparing treprostinil you (UT-15), described method comprises following steps:
(1) makes formula III a compound
P wherein
1Be allyl group, the benzyl that is unsubstituted or is substituted, ethanoyl, alkyl-carbonyl and SiR
aR
bR
c, R wherein
a, R
bAnd R
cBe C independently of one another
1-8Alkyl, phenyl, benzyl, the phenyl that is substituted or the benzyl that is substituted; And P
2As hereinbefore defined; With the cuprate reaction derived from formula II-1b compound
Wherein X, R
2, R
3And P
3As hereinbefore defined; Form formula 1b compound
(2) make the ketone group of formula 1b compound carry out methylenation, form the methylene compound of formula 2b
(3) make formula 2b compound carry out hydroboration with borane reagent (for example 9-boron dicyclo [3,3,1] nonane), then carry out oxidation with alkaline hydrogen peroxide, obtain the alkylol cpd of formula 3b
(4) in the presence of alkali, make formula 3b compound carry out sulfonylation with alkylsulfonyl donor (for example methane sulfonyl chloride or Tosyl chloride), form formula 4b compound
X wherein
1Be alkylsulfonyl;
(5) remove P
1Group forms formula 5b compound;
(6) make formula 5b compound carry out alkylation in the molecule, form formula 6b compound
(7) remove P
2And P
3Group forms formula 8d compound
(8) use alkylating agent XCH
2CN or XCH
2COOR
5(wherein X is halogen, for example Cl, Br or I; R
5Be alkyl) make phenolic group carry out alkylation, form formula 9d compound
Wherein Z be-CN or-COOR
5With
(9) with basic hydrolysis formula 9d compound-CN or-COOR
5Group forms the treprostinil that.
According to another embodiment, the invention provides the alternative method of another kind of preparation high purity formula 8d compound,
Described method comprises following steps:
(1) in the presence of the alkali of for example pyridine, triethylamine, sodium hydride or potassium hydride KH, with acry radical donor (for example diacetyl oxide, Acetyl Chloride 98Min., benzoyl oxide, Benzoyl chloride or 4-dibenzoyl chlorine) esterification formula 6d compound, forms the ester cpds of formula 10d
Wherein M is low alkyl group or the phenyl that is unsubstituted or is substituted; M is preferably methyl, phenyl or 4-phenyl;
(2) remove P
2And P
3Group forms the crystalline compounds of formula 11d
(3) make the two keys in the ω side chain of formula 11d compound carry out hydrogenation and make the compound of hydrogenation carry out deacylation; Or at first make formula 11d compound carry out deacylation and make subsequently the two keys in the ω side chain of the compound of deacylation carry out hydrogenation, form formula 8d compound.
The invention still further relates to a kind of formula 1d compound of novelty
Wherein
Be singly-bound or two key; R
2Be singly-bound or C
1-4Alkylidene group or formula-CH
2The group of O-; R
3Be C
1-7Alkyl or aryl or aralkyl, it is unsubstituted or separately through C
1-4Alkyl, halogen or trihalogenmethyl replace; P
1Be the benzyl that is unsubstituted or is substituted; P
2'And P
3'Be respectively the P of the protecting group that is defined as mentioned hydroxyl
2And P
3Or be H independently of one another.Work as P
2'And P
3'Be respectively P
2And P
3The time, its tool alkaline stability, and can be independently selected from methoxymethyl, methoxyl group thiomethyl, 2-methoxy ethoxy methyl, two (2-chloroethoxy) methyl, THP trtrahydropyranyl, tetrahydro thiapyran base, 4-methoxyl group THP trtrahydropyranyl, 4-methoxyl group tetrahydro thiapyran base, tetrahydrofuran base, tetrahydrochysene thio-furan base, 1-ethoxyethyl group, 1-methyl isophthalic acid-methoxy ethyl, trityl group and SiR
aR
bR
c, R wherein
a, R
bAnd R
cBe C independently of one another
1-8Alkyl, phenyl, benzyl, the phenyl that is substituted or the benzyl that is substituted.
The invention still further relates to a kind of formula 8D-1 crystalline compounds of novelty
Wherein Z is-CN.
The invention still further relates to a kind of formula 11-1 compound of novelty
Wherein M is methyl, phenyl or 4-phenyl; And
Be singly-bound or two key.
Further specify the present invention with following instance, but be not intended to limit scope of the present invention.Any modification that the those skilled in the art can easily realize or change are in the scope of this specification sheets disclosure and the claim of enclosing.
Example 1
(2R, 3R, 4R)-2-(3-(benzyloxy) benzyl)-4-tertiary butyl dimethyl-silicon alcoxyl base-3-((S, E)-3-tertiary butyl dimethyl-silicon alcoxyl Ji Xin-1-thiazolinyl) cyclopentanone
12 liters of three-necked flask flames are dry and make its cooling.With (1E)-tributyl-stannane base-(3S)-tertiary butyl dimethyl-silicon alcoxyl base octene (520g, 0.98mol) and 4 liters of tetrahydrofuran (THF)s (THF) add in the reaction flask, then under-70 ℃, dropwise add n-Butyl Lithium (612ml, 1.6M is in hexane).Homogeneous solution in 1 liter of THF is cooled to-70 ℃ and add the reaction flask and continue 30 minutes from-10 ℃ when stirring with cupric cyanide (87.7g, 0.98mol) and lithium methide (490ml, 2M is in ether).Subsequently, continue 30 minutes-70 ℃ of lower solution of (R)-1-(3-benzyloxy) benzyl-5-oxo-3-tertiary butyl dimethyl-silicon alcoxyl basic ring amylene (200g, 0.49mol) in 1 liter of THF are added in the reaction mixture.With 5 liters of saturated ammonium chlorides (aqueous solution) cancellation reaction that contains 500ml ammonium hydroxide.Reaction mixture is separated and uses the ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.The output of title compound is 280g (88%).
1H-NMR(CDCl
3):δ7.43(d,2H),7.39(t,2H),7.32(t,1H),7.16(t,1H),6.81(d,1H),6.78(s,1H),6.73(d,1H),5.55(dd,1H),5.48(dd,1H),5.02(s,2H),4.10~4.02(m,2H),3.05(d,1H),2.80(d,1H),2.60(d,1H),2.42(dt,1H),2.30~2.25(m,1H),2.04(dd,1H),1.47~1.25(m,8H),0.92~0.77(m,21H),0.12~0.01(m,12H)
13C-NMR(CDCl
3):δ215.40,158.77,140.51,137.08,136.61,129.27,128.52,128.42,127.85,127.44,122.31,115.97,112.84,73.33,72.69,69.78,55.14,51.64,47.68.,38.49,33.28,31.85,25.89,25.09,22.62,18.22,18.04,14.05,-4.66,-4.67,-4.71
Example 2
(2R, 3R, 4R)-2-(3-(benzyloxy) benzyl)-4--triethyl silicane oxygen base-3-((S, E)-3-triethyl silicane oxygen Ji Xin-1-thiazolinyl) cyclopentanone
2 liters of three-necked flask flames are dry and make its cooling.(1E)-tributyl-stannane base-(3S)-triethyl silicane oxygen base octene (127g, 0.24mol) and 1 liter of THF are added in the reaction flask, then under-70 ℃, dropwise add n-Butyl Lithium (150ml, 1.6M is in hexane).Homogeneous solution in 50ml THF is cooled to-70 ℃ and add the reaction flask and continue 30 minutes from-10 ℃ when stirring with cupric cyanide (21.5g, 0.24mol) and lithium methide (120ml, 2M is in ether).Subsequently, continue 30 minutes-70 ℃ of lower solution of (R)-1-(3-benzyloxy) benzyl-5-oxo-3-triethyl silicane oxygen base-cyclopentenes (50g, 0.12mol) in 500ml THF are added in the reaction mixture.With 1.25 liters of saturated ammonium chlorides (aqueous solution) cancellation reaction that contains 125ml ammonium hydroxide.Reaction mixture is separated and uses the ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.The output of title compound is 75g (94%).
1H-NMR(CDCl
3):δ7.42(d,2H),7.37(t,2H),7.31(t,1H),7.15(d,1H),6.80(d,1H),6.77(s,1H),6.73(d,1H),5.57~5.48(m,2H),5.04(s,2H),4.10~4.02(m,2H),3.06(dd,1H),2.80(dd,1H),2.59(dd,1H),2.45(dt,1H),2.31~2.27(m,1H),2.05(dd,1H),1.49~1.27(m,8H),0.97~0.86(m,21H),0.64~0.55(m,12H)
13C-NMR(CDCl
3):δ215.50,158.77,140.47,137.07,136.40,129.26,128.51,128.49,127.82,127.42,122.28,115.95,112.81,73.10,72.84,69.76,55.02,51.34,47.79.,38.54,33.37,31.86,25.09,22.62,14.04,6.91,6.75,4.99,4.73
Example 3
(2R, 3R, 4R)-2-(3-(benzyloxy) benzyl)-4-tertiary butyl dimethyl-silicon alcoxyl base-3-((S)-3-tertiary butyl dimethyl-silicon alcoxyl Ji Xinji) cyclopentanone
25ml double-neck flask flame is dry and make its cooling.(S)-tertiary butyl (1-iodine oct-3-yl oxygen base) dimethylsilane (1.18g, 3.2mmol) and 11.8L ether are added in the reaction flask, then under-70 ℃, dropwise add tert-butyl lithium (3.75ml, 1.7M is in pentane).Homogeneous solution in the 5.8ml ether is cooled to-70 ℃ and add the reaction flask and continue 30 minutes from room temperature when stirring with cupric cyanide (0.29g, 3.2mmol) and lithium methide (1.6ml, 2M is in ether).Subsequently, continue 30 minutes-70 ℃ of lower (R)-2-(3-(benzyloxy) the benzyl)-solution of 4-(tertiary butyl dimethylsilyl oxygen base) ring penta-2-ketenes (0.65g, 1.6mmol) in the 6.5ml ether are added in the reaction mixture.With 40ml saturated ammonium chloride (aqueous solution) the cancellation reaction that contains 0.4ml ammonium hydroxide.Reaction mixture is separated and uses the ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.The output of title compound is 1.1g (85%).
1HNMR(500MHz,CDCl
3)δ0.00~0.10(12H,m),0.88~0.91(21H,m),1.19~1.49(12H,m),1.91(1H,m),1.49~2.17(2H,m),2.58(1H,dd,J=6,17.5Hz),2.86(1H,ab),3.02(1H,ab),3.50(1H,m),4.09(1H,q,J=5.5Hz),5.04(2H,s),6.77-6.84(3H,m),7.19(1H,t,J=7.5Hz),7.33(1H,m),7.39(2H,m),7.44(2H,m)
13CNMR(125MHz,CDCl
3)δ-4.8,-4.5,-4.43,-4.41,14.0,17.9,18.0,22.6,24.8,25.8,25.9,27.9,32.0,33.9,35.9,37.1,47.5,48.7,54.8,69.8,72.3,73.4,112.7,115.7,121.9,127.4,127.8,128.5,129.4,137.0,141.3,158.8,217.6
Example 4
(2R, 3R, 4R)-2-(3-(tertiary butyl dimethyl-silicon alcoxyl base) benzyl)-4-(tetrahydrochysene-2H-pyrans-2-base oxygen base)-3-((S, E)-3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) suffering-1-thiazolinyl) cyclopentanone
2 liters of three-necked flask flames are dry and make its cooling.(1E)-iodo-(3S)-(tetrahydrochysene-2H-pyrans-2-base oxygen base)-1-octene (5.84g, 17mmol) and 50ml ether are added in the reaction flask, then under-70 ℃, dropwise add n-Butyl Lithium (12ml, 1.6M is in hexane).2.35g pentynyl-the copper and the solution of 5.87g three (dimethylamino) phosphine in the 30ml ether that add previous preparation.Mixture kept under this temperature 30 minutes again, and continue 30 minutes-70 ℃ of lower (R)-1-(3-(tertiary butyl dimethyl-silicon alcoxyl base) benzyl)-5-oxo-3-(tetrahydrochysene-2H-pyrans-2-base oxygen the base)-solution of cyclopentenes (5.66g, 15mmol) in 500ml THF are added in the reaction mixture.With 100ml saturated ammonium chloride (aqueous solution) the cancellation reaction that contains 10ml ammonium hydroxide.Reaction mixture is separated and uses the ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.The output of title compound is 6.65g (75%).
Example 5
((S, E)-1-((1R, 2R, 5R)-2-(3-(benzyloxy) benzyl)-3-methylene radical-5-(tertiary butyl dimethyl-silicon alcoxyl base) cyclopentyl) suffering-1-alkene-3-base oxygen base) (tertiary butyl) dimethylsilane
With Zn-CH
2Br
2-TiCl
4(500ml, 0.6M is in THF) and 100ml methylene dichloride (CH
2Cl
2) methylenation solution add in 5 liters of three-necked flasks in the ice-water bath.To containing (2R through the middle adding that stirs the mixture, 3R, 4R)-1 liter of CH of 2-(3-(benzyloxy) benzyl)-4-tertiary butyl dimethyl-silicon alcoxyl base-3-((S, E)-3-tertiary butyl dimethyl-silicon alcoxyl Ji Xin-1-thiazolinyl) cyclopentanone (200g, 0.307mol)
2Cl
2After 10 minutes, remove cooling bath and under room temperature (25 ℃), stirred the mixture 1.5 hours.Subsequently, with 1 liter of ethyl acetate and 500ml saturated sodium bicarbonate aqueous solution dilution mixture.Reaction mixture is separated and uses the ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.The output of title compound is 179.4g (90%).
1H-NMR(CDCl
3):δ7.44(d,2H),7.39(t,2H),7.33(t,1H),7.17(t,1H),6.84(s,1H),6.80(d,2H),5.48~5.39(m,2H),5.04(s,2H),4.88(s,1H),4.66(s,1H),4.04(q,1H),3.87(q,1H),2.95(dd,1H),2.68(dd,1H),2.60(dd,1H),2.51~2.47(m,1H),2.31~2.21(m,2H),1.32~1.26(m,8H),0.91~0.86(m,21H),0.05~0.01(m,12H)
13C-NMR(CDCl
3):δ158.64,150.94,142.36,137.18,135.20,130.20,128.98,128.51,127.83,127.43,122.22,116.04,112.11,107.01,72.95,69.82,55.70,48.03.,42.73,39.20,38.57,31.85,25.92,25.89,25.14,22.83,18.23,18.11,14.06,-4.17,-4.56,-4.74
Example 6
((S)-1-((1R, 2R, 5R)-2-(3-(benzyloxy) benzyl)-3-methylene radical-5-(tertiary butyl dimethyl-silicon alcoxyl base) cyclopentyl) oct-3-yl oxygen base) (tertiary butyl) dimethylsilane
With Zn-CH
2Br
2-TiCl
4(6ml, 0.6M is in THF) and 3.3ml methylene dichloride (CH
2Cl
2) methylenation solution add in the 25ml double-neck flask in the ice-water bath.To containing (2R through the middle adding that stirs the mixture, 3R, 4R)-the 10ml CH of 2-(3-(benzyloxy) benzyl)-4-(tertiary butyl dimethylsilyl oxygen base)-3-((S)-3-(tertiary butyl dimethylsilyl oxygen base) octyl group) cyclopentanone (1.1g, 1.68mmol)
2Cl
2After 10 minutes, remove cooling bath and under room temperature (25 ℃), stirred the mixture 1.5 hours.Dilute mixture and filter to remove throw out with 20ml EtOAc until reaction is finished.Extract filtrate with EtOAc, through MgSO
4Drying and evaporation.By using hexane-EtOAc as the silica gel column chromatography purifying gained resistates of scrub solution, obtain title compound: 0.85g (productive rate: 78%).
1HNMR(500MHz,CDCl
3)δ0.00~0.12(12H,m),0.90~0.94(21H,m),1.26~1.46(12H,m),1.68(1H,m),2.32~2.40(2H,m),2.58(1H,dd,J=6,15.5Hz),2.79~2.91(2H,m),3.53(1H,m),3.85(1H,q,J=5.5Hz),4.68(1H,s),4.90(1H,s),5.07(2H,s),6.82-6.88(3H,m),7.21(1H,t,J=7.5Hz),7.35(1H,m),7.41(2H,t,J=7Hz),7.47?(2H,m)
13CNMR(125MHz,CDCl
3)δ-4.7,-4.41,-4.38,14.1,18.0,18.2,22.7,25.0,25.5,25.9,28.6,32.1,34.6,37.1,41.9,42.6,49.1,52.3,69.8,72.3,72.6,107.5,112.1,116.0,122.1,127.4,127.8,128.5,129.0,137.2,142.8,152.4,158.7
Example 7
(1R, 2R, 3R)-3-(3-(benzyloxy) benzyl)-2-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-4-methylene basic ring-amylalcohol
With Zn-CH
2Br
2-TiCl
4(80ml, 0.6M is in THF) and 10ml methylene dichloride (CH
2Cl
2) solution add in the 500ml three-necked flask in the ice-water bath.To contain (1R, 2R, 3R)-1-(3-benzyloxy) benzyl-5-oxo-3-triethyl silicane oxygen base-2-[(3S)-triethyl silicane Oxy-1-octenyl through the middle adding that stirs the mixture]-the 100ml CH of pentamethylene (20g, 30.7mmol)
2Cl
2After 10 minutes, remove cooling bath and under room temperature (25 ℃), stirred the mixture 1.5 hours.Subsequently, with 150ml ethyl acetate and 50ml saturated sodium bicarbonate aqueous solution dilution mixture.Reaction mixture is separated and uses the ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Resistates further is dissolved in 100ml acetone and the 20ml water, then adds 0.5g tosic acid monohydrate.Reaction soln at room temperature stirred 1 hour and further stood vacuum-evaporation until form the layer of two separation.Add the 1.5L ethyl acetate in the reactant and reactant is separated.Organic layer through anhydrous magnesium sulfate drying, and is evaporated to drying with saturated sodium bicarbonate solution and salt water washing.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.The output of title compound is 12.83g, contains the 15-epimer of trace.Remove the 15-epimer by crystallization from ether/hexane.Acquisition is the 9.7g title compound (white is to pale powder) of crystallized form.Fusing point: 58 ℃.
1H-NMR(CDCl
3):δ7.43(d,2H),7.38(t,2H),7.32(t,1H),7.15(t,1H),6.81~6.76(m,3H),5.45~5.29(m,2H),5.03(s,2H),4.95(s,1H),4.81(s,1H),3.92(q,1H),3.80(q,1H),2.85~2.69(m?3H),2.55~2.52(m,1H),2.30~2.24(m,1H),2.10(q,1H),1.45~1.25(m,8H),0.87(t,3H)
13C-NMR(CDCl
3):δ158.68,149.97,141.77,137.08,135.83,132.14,129.02,128.55,127.90,127.45,122.24,116.22,112.19,107.76,75.33,72.73,69.86,56.67,48.11.,41.09,?39.13,37.14,31.73,25.16,22.59,14.03
Example 8
((S, E)-1-((1R, 2R, 5R)-2-(3-(benzyloxy) benzyl)-3-methylene radical-5-(tertiary butyl dimethyl-silicon alcoxyl base) cyclopentyl) suffering-1-alkene-3-base oxygen base) (tertiary butyl) dimethylsilane
With (1R, 2R, 3R)-3-(3-(benzyloxy) benzyl)-2-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-4-methylene radical cyclopentanol (12.7g, 64mmol) be dissolved in the 300ml ethyl acetate, add imidazoles (22g, 320mmol), and stirring is until reactive system becomes homogeneous.Tertiary butyl dimethylsilyl muriate (24g, 160mmol) is added in the reaction mixture.Make the reaction mixture through stirring reach room temperature and stirred overnight.Subsequently, reaction mixture is further used the salt water washing with 300ml saturated sodium bicarbonate aqueous solution washed twice, through anhydrous magnesium sulfate drying, filter, and concentrated, obtain crude product.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Productive rate: 80%.
1H-NMR(CDCl
3):δ7.44(d,2H),7.39(t,2H),7.33(t,1H),7.17(t,1H),6.84(s,1H),6.80(d,2H),5.48~5.39(m,2H),5.04(s,2H),4.88(s,1H),4.66(s,1H),4.04(q,1H),3.87(q,1H),2.95(dd,1H),2.68(dd,1H),2.60(dd,1H),2.51~2.47(m,1H),2.31~2.21(m,2H),1.32~1.26(m,8H),0.91~0.86(m,21H),0.05~0.01(m,12H)
13C-NMR(CDCl
3):δ158.64,150.94,142.36,137.18,135.20,130.20,128.98,128.51,127.83,127.43,122.22,116.04,112.11,107.01,72.95,69.82,55.70,48.03.,42.73,39.20,38.57,31.85,25.92,25.89,25.14,22.83,18.23,18.11,14.06,-4.17,-4.56,-4.74
Example 9
((1S, 2S, 3R, 4R)-2-(3-(benzyloxy) benzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl) cyclopentyl) methyl alcohol
Will be through degassed (1R, 2R, 3R)-1-(3-benzyloxy) benzyl-3-tertiary butyl-two-siloxy base-2-[(3S)-tertiary butyl dimethylsilane Oxy-1-octenyl]-5-methylene radical-pentamethylene (160g, 0.246mol) solution in 1.6 liters of anhydrous THF is cooled to 0 ℃ under nitrogen, dropwise added 9-boron dicyclo [3 through 5 minutes, 3,1] nonane (1280ml, 0.5M is in THF).With colourless solution 0 ℃ of lower stirred overnight and use successively 30% hydrogen peroxide (640ml) and 3N potassium hydroxide (640ml) is processed.Gained suspension is 0 ℃ of lower restir 30 minutes, and stirs 75 minutes when being warmed up to room temperature.Reaction mixture is transferred in the separating funnel, with 3 liters of salt solution and 1 liter of ethyl acetate dilution.Reaction mixture is separated and uses the ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Productive rate: 97%.
1H-NMR(CDCl
3):δ7.45~7.29(m,5H),7.17(t,1H),6.83~6.77(m,3H),5.50~5.35(m,2H),5.03(s,2H),4.13~4.02(m,2H),3.77(t,1H),3.61(d,1H),3.42(d,1H),2.80~2.75(m,1H),2.43~2.39(m,2H),2.05~1.86(m,4H),1.66~1.26(m,8H),0.90~0.84(m,21H),0.08~0.00(m,12H)
13C-NMR(CDCl3):δ158.74,143.51,137.07,135.03,131.13,129.22,128.52,127.86,127.43,121.30,115.22,111.86,79.11,73.05,69.80,63.62,58.59,49.44.,41.45,40.58,38.63,31.83,25.91,25.76,25.12,22.64,18.29,17.87,14.66,-4.22,-4.45,-4.83
Example 10
((1S, 2S, 3R, 4R)-2-(3-(benzyloxy) benzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S)-3-(tertiary butyl dimethyl-silicon alcoxyl base) octyl group) cyclopentyl) methyl alcohol
Will be through degassed ((1R, 2R, 3R)-and 3-(3-(benzyloxy) benzyl)-2-((S)-3-(tertiary butyl dimethylsilyl oxygen base) octyl group)-4-methylene radical cyclopentyloxy) (tertiary butyl) dimethylsilane (0.75g, 1.15mmol) solution in the anhydrous THF of 8ml is cooled to 0 ℃ under nitrogen, and with 9-boron dicyclo [3,3,1] nonane (6.9ml, 0.5M is in THF) dropwise adds in the mixture.Colourless solution is 0 ℃ of lower stirred overnight and use successively 30% hydrogen peroxide (3ml) and 3N potassium hydroxide (3ml) processing.Gained suspension at room temperature stirred 1 hour.Extract mixture with EtOAc, and organic layer is with the water washing of 20ml salt, through MgSO
4Drying and evaporation.By using hexane-EtOAc as the silica gel column chromatography purifying gained resistates of scrub solution, obtain title compound: 0.6g (productive rate 78%).
1HNMR(500MHz,CDCl
3)δ0.02~0.12(12H,m),0.90~0.92(21H,m),1.22~1.43(9H,m),1.55~1.57(2H,m),1.72~1.74(2H,m),1.92~2.07(4H,m),2.80~2.94(2H,m),3.50~3.57(2H,m),3.63(1H,dd,J=3,11Hz),3.76(1H,br)3.96(1H,d,J=6.5Hz),5.05(2H,s),6.81(1H,dd,J=2,8Hz),6.87(2H,m),7.19(1H,t,J=8Hz),7.33(1H,m),7.39(2H,t,J=7.5Hz),7.44(2H,m)
13CNMR(125MHz,CDCl
3)δ-4.7,-4.5,-4.43,-4.41,14.0,17.8,18.1,22.6,24.8,25.7,25.9,29.9,32.0,35.2,35.9,37.1,40.2,42.5,48.5,54.9,63.7,69.8,72.5,79.2,111.9,115.3,121.4,127.4,127.8,128.5,129.2,137.1,143.7,158.8
Example 11
Methanesulfonic ((1S, 2S, 3R, 4R)-2-(3-(benzyloxy) benzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl) cyclopentyl) methyl esters
Under nitrogen with ((1S, 2S, 3R, 4R)-2-(3-(benzyloxy) benzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S, E)-and 3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl) cyclopentyl) methyl alcohol (50g, 0.075mol) is in anhydrous CH
2Cl
2Solution (500ml) is cooled to 0 ℃ and use successively triethylamine (31.3ml, 0.225mol) and methane sulfonyl chloride (11.6ml, 0.15mol) is processed.Pour into mixture in the saturated sodium bicarbonate aqueous solution and stirred 30 minutes.Reaction mixture is separated and with 500ml ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Productive rate: 81%.
1H-NMR(CDCl
3):δ7.45~7.29(m,5H),7.19(t,1H),6.82~6.78(m,3H),5.48~5.33(m,2H),5.05(s,2H),4.38(dd,1H),4.28~4.22(m,1H),4.05~3.96(m,2H),2.89(s,3H),2.80(dd,1H),2.52(dd,1H),2.29~2.20(m,2H),2.11~2.02(m,1H),1.68~1.59(m,2H),1.44~1.24(m.,8H),0.89~0.67(m,21H),0.07~0.00(m,12H)
Example 12
4-toluene sulfonic acide ((1S, 2S, 3R, 4R)-2-(3-(benzyloxy) benzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl) cyclopentyl) methyl esters
Under nitrogen with ((1S, 2S, 3R, 4R)-2-(3-(benzyloxy) benzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S, E)-and 3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl) cyclopentyl) methyl alcohol (15g, 0.023mol) is in anhydrous CH
2Cl
2Solution (500ml) is cooled to 0 ℃ and use successively triethylamine (9.6ml, 0.068mol) and Tosyl chloride (8.77g, 0.046mol) is processed.Pour into mixture in the saturated sodium bicarbonate aqueous solution and stirred 30 minutes.Reaction mixture is separated and with 500ml ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Productive rate: 85%.
1H-NMR(CDCl
3):δ7.72(d,2H),7.46~7.29(m,8H),7.13(t,1H),6.80~6.64(m,3H),5.57~5.32(m,2H),5.04(s,2H),4.15~3.88(m,4H),2.67(dd,1H),2.41(m,4H),2.17~1.94(m,4H),1.49~1.28(m,8H),0.92~0.82(m,21H),0.04~0.00(m,12H)
13C-NMR(CDCl3):δ158.86,144.53,142.20,137.10,135.60,133.05,130.20,129.78,128.53,127.88,127.86,127.48,121.19,115.06,112.23,78.00,72.87,69.83,56.22,46.62.,38.56,38.00,37.85,34.50,31.81,25.88,25.83,25.62,25.06,22.61,21.59,18.22,17.93,14.03,-4.23,-4.61,-4.77
Example 13
4-toluene sulfonic acide ((1S, 2S, 3R, 4R)-2-(3-(benzyloxy) benzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S)-3-(tertiary butyl dimethyl-silicon alcoxyl base) octyl group) cyclopentyl) methyl esters
Under nitrogen with ((1S, 2S, 3R, 4R)-and 2-(3-(benzyloxy) benzyl)-4-(tertiary butyl dimethylsilyl oxygen base)-3-((S)-3-(tertiary butyl dimethylsilyl oxygen base) octyl group) cyclopentyl) methyl alcohol (0.3g, 0.45mmol) is in anhydrous CH
2Cl
2Solution (3ml) is cooled to 0 ℃ and with triethylamine (0.12ml, 0.9mmol) and trace 4-(dimethylamino) pyridine (DMAP) processing, add subsequently Tosyl chloride (0.13g, 0.67mmol) and reaction stirred at room temperature.After reaction is finished, add the saturated NaHCO of 20ml
3And use CH
2Cl
2Extraction is through MgSO
4Drying and evaporation.By using hexane-EtOAc as the silica gel column chromatography purifying gained resistates of scrub solution, obtain title compound (0.2g, productive rate 54%).
1HNMR(500MHz,CDCl
3)δ-0.03~0.04(12H,m),0.85~0.90(21H,m),1.06~1.09(2H,m),1.17~1.30(8H,m),1.48(1H,m),1.55(1H,m),1.90~1.95(3H,m),2.28(1H,q,J=7Hz),2.41(3H,s),2.49~2.59(3H,m),3.45(1H,m),3.82(1H,m),4.07~4.18(2H,m),5.04(2H,s),6.70(1H,d,J=7.5Hz),6.76(1H,s),6.79(1H,m),7.15(1H,t,J=8Hz),7.29~7.34(3H,m),7.39(2H,t,J=5.5Hz),7.45(2H,m),7.65(2H,d,J=8Hz)
13CNMR(125MHz,CDCl
3)δ-4.8,-4.45,-4.41,14.0,17.8,18.1,21.6,22.6,24.8,25.82,25.88,25.91,29.0,32.0,34.8,35.5,37.1,37.9,39.2,46.4,52.7,69.8,71.8,72.4,78.3112.2,115.4,121.6,127.4,127.9,128.51,128.54,129.2,129.8,133.0,137.1,142.4,144.6,158.8
Example 14
Methanesulfonic ((1S, 2S, 3R, 4R)-2-(3-hydroxybenzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl) cyclopentyl) methyl esters
With methanesulfonic ((1S, 2S, 3R, 4R)-2-(3-(benzyloxy) benzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S, E)-and 3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl) cyclopentyl) methyl esters (45g, 0.06mol) solution in anhydrous methanol (450ml) uses potassium hydroxide (9.72g, 0.18mol) and 5%Pd/C (13.5g, 30 % by weight) to process under hydrogen successively 2 hours.Subsequently, filter reaction mixture with Celite pad.Concentrated filtrate obtains crude product (50g).
1H-NMR(CDCl
3):δ7.11(t,1H),6.73(d,1H),6.68(s,1H),6.64(d,1H),5.45~5.34(m,2H),5.28(brs,1H),4.28~4.24(m,1H),4.10~4.02(m,2H),3.97~3.93(m,1H),2.71(dd,1H),2.53(dd,1H),2.26~2.22(m,2H),2.05~1.98(m,5H),1.61~1.57(m,1H),1.44~1.25(m,10H),0.92~0.85(m,21H),0.11~0.02(m,12H)
Example 15
4-toluene sulfonic acide ((1S, 2S, 3R, 4R)-2-(3-hydroxybenzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl) cyclopentyl) methyl esters
With 4-toluene sulfonic acide ((1S, 2S, 3R, 4R)-2-(3-(benzyloxy) benzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S, E)-and 3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl) cyclopentyl) methyl esters (15.7g, 0.019mol) solution in anhydrous methanol (150ml) uses potassium hydroxide (3.25g successively under hydrogen, 0.057mol) and 5%Pd/C (6.28g, 40 % by weight) processed 5 hours.Subsequently, filter reaction mixture with Celite pad.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Productive rate: 90%.
1H-NMR(CDCl
3):δ.7.81(d,2H),7.35(d,2H),7.05(t,1H),6.69(d,1H),6.66(d,1H),6.06(s,1H),5.79~5.68(m,2H),4.19~4.16(m,1H),4.01~3.95(m,2H),3.34(t,1H),2.77?(dd,1H),2.64(t,1H),2.45~2.39(m,4H),2.18~2.13(m,1H),2.08~2.00(m,2H),1.78~1.73(m,1H),1.68~1.16(m,1H),1.41~1.21(m,8H),0.91~0.81(m,21H),0.10~-0.01(m,12H)
Example 16 and 17
4-toluene sulfonic acide ((1S, 2S, 3R, 4R)-2-(3-hydroxybenzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S)-3-(tertiary butyl dimethyl-silicon alcoxyl base) octyl group) cyclopentyl) methyl esters
Example 16: with 4-toluene sulfonic acide ((1S, 2S, 3R, 4R)-2-(3-(benzyloxy) benzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S, E)-and 3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl) cyclopentyl) methyl esters (15.7g, 0.019mol) solution in anhydrous methanol (150ml) at room temperature uses potassium hydroxide (3.25g successively under hydrogen, 0.057mol) and 5%Pd/C (6.28g, 40 % by weight) processed 6 hours and 50 ℃ of lower processing 24 hours.Subsequently, filter reaction mixture with Celite pad.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Output: 72%.
Example 17: with 4-toluene sulfonic acide ((1S, 2S, 3R, 4R)-and 2-(3-(benzyloxy) benzyl)-4-(tertiary butyl dimethylsilyl oxygen base)-3-((S)-3-(tertiary butyl dimethylsilyl oxygen base) octyl group) cyclopentyl) methyl esters (0.15g, 0.18mmol) solution in anhydrous methanol (2ml) at room temperature uses potassium hydroxide (0.03g successively under hydrogen, 0.54mmol) and 5%Pd/C (0.045g, 30 % by weight) processed 2 hours.After reaction is finished, use the Celite pad filtering mixt, and evaporated filtrate.By using hexane-EtOAc as the silica gel column chromatography purifying gained resistates of scrub solution, obtain title compound (0.12g, productive rate 90%).
1HNMR(500MHz,CDCl
3)δ-0.01~0.10(12H,m),0.79~0.91(21H,m),1.12~1.46(12H,m),1.90(1H,m),2.02(1H,m),2.28(1H,m),2.31(1H,s),2.43(3H,s),2.54~2.72(3H,m),3.49~3.58(2H,m),3.91(1H,m),4.08(1H,m),6.60~6.72(3H,m),7.11(1H,m),7.22(1H,d,J=10Hz),7.32(1H,m),7.72~7.78(2H,m)
13CNMR(125MHz,CDCl
3)δ-4.3,-3.6,-3.0,14.1,18.0,18.1,22.6,22.7,25.2,25.325.7,25.8,30.3,31.9,35.1,35.6,37.3,37.4,41.0,48.3,51.1,66.5,71.8,80.0,113.0,115.8,120.9,126.7,127.8,129.6,129.89,129.93,143.7,155.9
Example 18 and 19
(1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-(tertiary butyl dimethyl-silicon alcoxyl base)-1-((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-phenol
Example 18: lower to 60% sodium hydride (7.2g at-40 ℃ under nitrogen, 0.18mol) process through degassed methanesulfonic ((1S, 2S, 3R, 4R)-2-(3-hydroxybenzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S, E)-and 3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl) cyclopentyl) solution of methyl esters (50g, crude compound) in anhydrous glyme (500ml).Gained suspension is subsequently-40 ℃ of lower stirrings 40 minutes, then 0 ℃ of lower stirring 15 minutes.The suspension restir was warmed up to room temperature in 20 minutes simultaneously and under refluxing, stirred 2.5 hours subsequently.Reactant is cooled to 10 ℃ subsequently, with ice-cold salt solution (250ml) and ethyl acetate (500ml) dilution.Reaction mixture is separated and uses the ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Productive rate: 75%.
Example 19: lower to 60% sodium hydride (2.04g at 0 ℃ under nitrogen, 0.051mol) process through degassed 4-toluene sulfonic acide ((1S, 2S, 3R, 4R)-2-(3-hydroxybenzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S, E)-and 3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl) cyclopentyl) solution of methyl esters (12.6g, 0.017mol) in anhydrous THF (250ml).Gained suspension stirred 4 hours under refluxing.Reactant is cooled to 10 ℃ subsequently, with ice-cold salt solution (250ml) and ethyl acetate (500ml) dilution.Reaction mixture is separated and uses the ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Productive rate: 90%.
1H-NMR(CDCl
3):δ7.00(t,1H),6.69(d,1H),6.65(d,1H),5.48~5.46(m,2H)4.70(brs,1H),4.11~4.08(m,1H),3.78~3.75(m,1H),2.70~2.62(m,2H),2.52~2.38(m,2H),2.38~2.20(m,1H),2.16~2.04(m,2H),2.02~1.81(m,2H),1.42~1.25(m,8H),0.90~0.84(m,21H),0.06~0.00(m,12H)
13C-NMR(CDCl3):δ152.40,140.99,135.10,130.58,126.23,124.44,120.71,112.90,73.08,55.86,41.40.,39.80,38.65,32.56,31.85,25.94,25.91,25.19,22.65,18.27,18.19,14.07,-4.19,-4.55,-4.73
Example 20
(1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-(tertiary butyl dimethyl-silicon alcoxyl base)-1-((S)-3-(tertiary butyl dimethyl-silicon alcoxyl base) octyl group)-1H-cyclopenta [b] naphthalene-5-phenol
Lower to 60% sodium hydride (2.04g at 0 ℃ under nitrogen, 0.051mol) process through degassed 4-toluene sulfonic acide ((1S, 2S, 3R, 4R)-and 2-(3-hydroxybenzyl)-4-(tertiary butyl dimethyl-silicon alcoxyl base)-3-((S)-3-(tertiary butyl dimethyl-silicon alcoxyl base) octyl group) cyclopentyl) solution of methyl esters (12.4g, 0.017mol) in anhydrous THF (250ml).Gained suspension stirred 4 hours under refluxing.Reactant is cooled to 10 ℃ subsequently, with ice-cold salt solution (250ml) and ethyl acetate (500ml) dilution.Reaction mixture is separated and uses the ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Productive rate: 87%.
1H-NMR(CDCl
3):δ7.00(t,1H),6.73(d,1H),6.63(d,1H),4.67(brs,1H),3.69~3.62(m,1H),2.83~2.74(m,2H),2.49~2.35(m,2H),2.19~2.05(m,3H),1.83~1.81(m,1H),1.43~1.21(m,13H),0.97~0.86(m,21H),0.56~0.00(m,12H)
13C-NMR(CDCl
3):δ152.06,141.50,126.13,124.72,120.32,112.82,72.76,52.61,41.32,40.42,37.01,34.85,34.31,33.27,32.07,28.01,26.38,25.96,25.90,24.98,22.67,18.17,18.03,14.07,-4.25,-4.34,-4.72
Example 21 and 22
(1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-1-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-2,5-diphenol
Example 21: at room temperature use tetrabutyl ammonium fluoride (180ml, 1M is in THF) processing (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9, ((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl)-naphthalene-5-phenol (10g, 0.018mmol) whole night for 1H-cyclopenta [b] for 9a-six hydrogen-2-(tertiary butyl dimethyl-silicon alcoxyl base)-1-.Pour into reaction mixture in the saturated sodium bicarbonate aqueous solution (200ml) and stirred 30 minutes.Reaction mixture is separated and with 300ml ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Acquisition is the title compound of crystallized form.Productive rate: 70%.
Example 22: at room temperature with (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-(tertiary butyl dimethyl-silicon alcoxyl base)-1-((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-phenol (6.4g, 0.011mmol) is dissolved in THF (12.8ml), acetic acid (38.4ml) and the distilled water (12.8ml) whole night successively.Pour into reaction mixture in the saturated sodium bicarbonate aqueous solution (150ml) and stirred 30 minutes.Reaction mixture is separated and with 200ml ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Acquisition is the title compound (output: 88%) of crystallized form.
1H-NMR(CDCl
3):δ6.98(t,1H),6.70~6.64(m,2H),5.60(brs,1H),5.53~5.42(m,2H),4.11~4.05(m,1H),3.75~3.66(m,1H),2.64~2.56(m,4H),2.40~2.33(m,3H),2.17~2.16(m,1H),2.05~2.02(m,1H),1.50~1.32(m,8H),1.09~1.05(m,1H),0.90~0.88(m,3H)
13C-NMR(CDCl
3):δ152.81,140.47,135.98,133.13,126.26,124.37,120.58,113.18,75.70,73.33,56.52,45.13,40.36,37.10,32.52,31.90,31.66,25.58,25.20,22.61,14.01
Example 23
Acetic acid (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-hydroxyl-1-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-base ester
At room temperature use diacetyl oxide (0.1ml, 1.07mol) and DMAP (1.1mg, 0.09mmol) to process and contain (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-(tertiary butyl dimethyl-silicon alcoxyl base)-1-((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl)-toluene (5ml) of 1H-cyclopenta [b] naphthalene-5-phenol (0.5g, 0.89mmol) 30 minutes.Reactant extracts with saturated sodium bicarbonate aqueous solution (10ml) dilution and with ethyl acetate (10ml).Reaction mixture is separated and uses the ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Obtain 0.45g acetic acid (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-(tertiary butyl dimethyl-silicon alkoxyl group)-1-((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-base ester.Product is dissolved in the tetrahydrofuran (THF) (0.9ml) subsequently, and at room temperature uses acetic acid (2.7ml) and distilled water (0.9ml) to process whole night.Reactant is used subsequently saturated sodium bicarbonate aqueous solution (12ml) dilution and is extracted with ethyl acetate (15ml).Reaction mixture is separated and uses the ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Acquisition is the title compound of crystallized form.Fusion range is 54 ~ 65 ℃.Productive rate: 65%.
1H-NMR(CDCl
3):δ7.13(t,1H),6.96(d,1H),6.85(d,1H),5.39~5.38(m,2H),3.98~3.93(m,1H),3.62~3.56(m,1H),3.19(brs,2H),2.62(dd,1H),2.50(dd,1H),2.38(dd,1H),2.32~2.24(m,5H),2.14~2.09(m,1H),2.00~1.95(m,1H),1.70~1.66(m,1H),1.55~1.51(m,1H),1.43~1.29(m,8H),1.02(q,1H),0.89(t,3H)
13C-NMR(CDCl
3)δ169.63,148.10,140.71,136.11,133.34,130.57,126.32,125.66,119.47,75.48,73.05,56.65,40.13,40.02,36.89,32.20,32.00,31.64,27.02,25.11,22.55,20.71,13.94
Example 24
Phenylformic acid (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-hydroxyl-1-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-base ester
Lower to sodium hydride (0.29g at 0 ℃, 7.16mol) process and to contain 2g (3.58mmol, from example 18) (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-six hydrogen-2-(tertiary butyl dimethyl-silicon alkoxyl group)-1-((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl)-anhydrous tetrahydro furan (20ml) of 1H-cyclopenta [b] naphthalene-5-phenol (it contains 6% contraposition cyclisation isomer) and at room temperature stirring 10 minutes, then dropwise add Benzoyl chloride (0.63ml, 5.37mmol).After 30 minutes, reactant is cooled to 10 ℃, extracts with ice-cold salt solution (10ml) dilution and with ethyl acetate (10ml).Reaction mixture is separated and uses the ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Obtain 2.1g phenylformic acid (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-(tertiary butyl dimethyl-silicon alcoxyl base)-1-((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-base ester.Product is dissolved in the tetrahydrofuran (THF) (4.2ml) subsequently, and at room temperature uses acetic acid (12.6ml) and distilled water (4.2ml) to process whole night.Reactant is used subsequently saturated sodium bicarbonate aqueous solution (50ml) dilution and is extracted with ethyl acetate (60ml).Reaction mixture is separated and uses the ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Acquisition is the product of crystallized form.Fusing point: 140 ~ 141 ℃.Output: 68%.
By the further assay products of HPLC to determine not seeing contraposition cyclisation isomer in the crystallized product.
1H-NMR(CDCl
3):δ8.19(d,2H),7.63(t,1H),7.50(t,2H),7.18(t,1H),7.03(d,1H),6.99(d,1H),5.50~5.40(m,2H),4.04~4.00(m,1H),3.66~3.62(m,1H),3.04(brs,1H),2.88(brs,1H),2.68(dd,1H),2.56(dd,1H),2.44(dd,1H),2.38(dd,1H),2.32~2.28(m,1H),2.14~2.00(m,2H),1.76~1.71(m,1H),1.58~1.53(m,1H),1.48~1.32(m,7H),1.08(q,1H),0.90(t,3H)
13C-NMR(CDCl
3)δ165.31,148.44,140.86,136.22,133.60,133.21,130.83,130.19,129.38,128.60,126.49,125.80,119.70,75.69,73.06,53.73,40.14,37.10,32.29,32.11,31.72,27.12,25.18,22.62,14.01
Example 25
Phenylformic acid (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-hydroxyl-1-((S)-3-hydroxyl octyl group)-1H-cyclopenta [b] naphthalene-5-base ester
With 5%Pd/C (0.05g, 20 % by weight) processing contains phenylformic acid (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9, the anhydrous methanol (2.5ml) of 9a-six hydrogen-2-hydroxyl-1-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-base esters (0.35g, 0.8mmol) and under hydrogen, at room temperature stirring 5 hours.Subsequently, filter reaction mixture with Celite pad.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Productive rate: 87%.
1H-NMR(CDCl
3):δ8.20(d,2H),7.62(t,1H),7.50(t,2H),7.18(t,1H),7.05(d,1H),6.90(d,1H),3.73~3.66(m,1H),3.61~3.59(m,1H),2.80(dd,1H),2.64(dd,1H),2.51(dd,1H),2.34(dd,1H),2.23~2.18(m,1H),2.13~2.03(m,1H),1.92~1.86(m,2H),1.66~1.63(m,2H),1.56~1.52(m,2H),1.46~1.41(m,3H),1.32~1.16(m,7H),1.14~1.11(m,1H),0.88(t,3H)
13C-NMR(CDCl
3):δ165.16,148.30,141.09,133.52,131.03,130.18,129.51,128.58,126.39,125.56,119.60,75.52,52.32,41.25,37.44,34.94,33.72,32.59,31.89,28.56,27.38,25.34,22.61,14.00
Example 26
2-((1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-hydroxyl-1-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-base oxygen base) methyl acetate
Contain (1R with 50%NaOH (1g) processing, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-(tertiary butyl dimethyl-silicon alcoxyl base)-1-((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl)-methyl bromoacetate (3ml) of 1H-cyclopenta [b] naphthalene-5-phenol (0.5g, 0.89mmol).Mixture at room temperature stirred 60 minutes.Reaction mixture is cooled to 10 ℃ and slowly add 3N HCl until pH=7 uses the ethyl acetate extraction reactant subsequently.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Obtain 0.2g2-((1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-(tertiary butyl dimethyl-silicon alcoxyl base)-1-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-base oxygen base) methyl acetate.At room temperature product is dissolved in subsequently in THF (1.3ml), acetic acid (3.9ml) and the distilled water (1.3ml) whole night.Pour into reaction mixture in the saturated sodium bicarbonate aqueous solution (10ml) and stirred 30 minutes.Reaction mixture is separated and with 20ml ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Acquisition is the title compound (productive rate: 58%) of crystallized form.
Example 27 ~ 30
(1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-1-((S)-3-hydroxyl octyl group)-1H-cyclopenta [b] naphthalene-2,5-diphenol
Example 27:
Repeat and program identical described in the example 22, wherein exception for use in the reaction to wait mole matrix be (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-six hydrogen-2-(tertiary butyl dimethyl-silicon alcoxyl base)-1-((S)-3-(tertiary butyl dimethyl-silicon alcoxyl base) octyl group)-1H-cyclopenta [b] naphthalene-5-phenol (from example 20) but not (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-six hydrogen-2-(tertiary butyl dimethyl-silicon alcoxyl base)-1-((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-phenol.Preparation title compound and obtain with crystallized form.(productive rate: 83%).
Example 28: under hydrogen, at room temperature use successively potassium hydroxide (0.5g, 0.008mol) and 5%Pd/C (0.5g, 20 % by weight) to process and contain (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-six hydrogen-1-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-2,5-diphenol (2.5g, 0.008mol, from example 21 or 22) anhydrous methanol (25ml) whole night.Filter reaction mixture with Celite pad subsequently.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Acquisition is the title compound of crystallized form.Productive rate: 72%.
Example 29: process phenylformic acid (1R with 1mL sodium hydroxide (5% in methyl alcohol), 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-six hydrogen-2-hydroxyl-1-((S)-3-hydroxyl octyl group)-1H-cyclopenta [b] naphthalene-5-base ester (0.2g, 0.008mol, from example 25), at room temperature stirred subsequently 60 minutes.With 3NHCl (1ml) and ethyl acetate (10mL) diluted reaction mixture.Reaction mixture is separated and uses the ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Acquisition is the title compound of crystallized form.Productive rate: 85%.
Example 30: contain phenylformic acid (1R, 2R with 5%Pd/C (0.05g, 20 % by weight) processing, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-hydroxyl-1-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-base ester (0.25g, 0.6mmol, from example 24) anhydrous methanol (2ml) and under hydrogen, at room temperature stirred 28 hours.Filter reaction mixture with Celite pad subsequently.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Acquisition is the title compound of crystallized form.Productive rate: 73%.
1H-NMR(CD
3OD):δ6.98(t,1H),6.62(d,2H),3.63~3.56(m,1H),3.52~3.51(m,1H),2.71~2.56(m,3H),2.49~2.42(m,1H),2.36~2.29(m,1H),2.07~2.03(m,1H),1.95~1.83(m,1H),1.76~1.50(m,3H),1.48~1.21(m,9H),1.20~1.02(m,2H),0.91(t,3H)
13C-NMR(CD
3OD):δ154.36,140.87,126.00,125.03,119.48,112.78,76.58,71.92,51.55,41.33,41.00,37.29,35.05,33.57,33.15,32.16,28.66,25.55,25.50,22.70,13.44
Example 31 and 32
2-((1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-hydroxyl-1-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-base oxygen base) acetonitrile
Example 31: use K
2CO
3(1.66g, 0.012mol), chloromethyl cyanide (0.51ml, 0.008mol) and Tetrabutyl amonium bromide (0.32g, 0.001mmol) process and to contain (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-1-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-2, the anhydrous propanone of 5-diphenol (1.6g, 0.004mol) (16ml).Mixture 30 ℃ of lower heating whole night.Filter reaction mixture with Celite pad subsequently.Vaporising under vacuum goes out filtrate.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Acquisition is the title compound of crystallized form.Productive rate: 89%.
Example 32: use K
2CO
3(6.64g, 0.048mol), chloromethyl cyanide (2ml, 0.032mol) and Tetrabutyl amonium bromide (1.28g, 0.004mmol) process and to contain (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9, the anhydrous propanone (64ml) of 9a-six hydrogen-2-(tertiary butyl dimethyl-silicon alcoxyl base)-1-((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-phenol (6.4g, 0.011mmol).Mixture 30 ℃ of lower heating whole night.Filter reaction mixture with Celite pad subsequently.Vaporising under vacuum goes out filtrate.Obtain rough benzindene nitrile [2-((1R through protection; 2R; 3aS; 9aS)-2,3,3a; 4; 9,9a-, six hydrogen-2-(tertiary butyl dimethyl-silicon alcoxyl base)-1-((S, E)-3-(tertiary butyl dimethyl-silicon alcoxyl base) suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-base oxygen base) acetonitrile].At room temperature rough benzindene nitrile through protection is dissolved in THF (19.2ml), acetic acid (57.6ml) and the distilled water (19.2ml) whole night successively subsequently.Pour into reaction mixture in the saturated sodium bicarbonate aqueous solution (200ml) and stirred 30 minutes.Reaction mixture is separated and with 300ml ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.The output of title compound is 3.43g, contains the contraposition cyclisation isomer of trace.Remove contraposition cyclisation isomer by crystallization from isopropyl ether/heptane.Obtain the title compound (white is to pale powder) that 2.74g is crystallized form.Fusing point: 58 ℃ of (productive rates: 67%).
1H-NMR(CDCl
3):δ7.15(t,1H),6.87(d,1H),6.83(d,1H),5.53~5.46(m,2H),4.76(s,2H),4.09~4.01(m,1H),3.76~3.70(m,1H),2.68~2.59(m,2H),2.43~2.32(m,2H),2.24~2.18(m,1H),2.07~2.03(m,1H),1.58~1.55(m,1H),1.51~1.48(m,1H),1.40~1.31(m,8H),1.07(q,1H),0.91(t,3H)
13C-NMR(CDCl
3):δ153.85,141.16,136.18,132.71,128.08,126.58,123.24,115.41,110.49,75.60,73.06,56.72,54.44,40.30,37.21,32.40,31.99,31.69,25.60,25.21,22.62,14.02
Example 33
2-((1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-hydroxyl-1-((S)-3-hydroxyl octyl group)-1H-cyclopenta [b] naphthalene-5-base oxygen base) acetonitrile
Use K
2CO
3(2.07g, 0.015mol), chloromethyl cyanide (0.64ml, 0.010mol) and Tetrabutyl amonium bromide (0.32g, 0.001mmol) process and to contain (1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-six hydrogen-1-((S)-3-hydroxyl octyl group)-1H-cyclopenta [b] naphthalene-2, the anhydrous propanone of 5-diphenol (2g, 0.005mol) (20ml).Mixture 30 ℃ of lower heating whole night.Filter reaction mixture with Celite pad subsequently.Vaporising under vacuum goes out filtrate.Mixture by using hexane and ethyl acetate is as the silica gel chromatography purification of crude product of gradient elution agent.Productive rate: 82%.
Example 34 and 35
2-((1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-hydroxyl-1-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-base oxygen base) acetic acid
Example 34: contain 2-((1R, 2R, 3aS with 20%KOH (5ml) processing, 9aS)-2,3,3a, 4,9,9a-six hydrogen-2-hydroxyl-1-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-base oxygen base) Virahol (16ml) of acetonitrile (1.6g, 0.004mol) and refluxing 3 hours, be cooled to subsequently 10 ℃, and slowly add 3N HCl until pH=8.Remove in a vacuum solvent.Add ethyl acetate and salt solution and slowly add 3N HCl until pH=2 subsequently.Use the ethyl acetate extraction reaction mixture.Acetic acid ethyl ester extract through merging is through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.By from ethanol/H
2Crystallization comes the purification of crude product among the O.Obtain the title compound that 1.2g is crystallized form.
Example 35:
Repeat the program described in example 29, wherein exception is 2-((1R for the mole matrix that waits of using in reaction, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-six hydrogen-2-hydroxyl-1-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-base oxygen base) methyl acetate.Preparation title compound and obtain with crystallized form.Productive rate: 82%.
1H-NMR(CD
3OD):δ7.06(t,1H),6.74(d,1H),6.71(d,1H),5.53(dd,1H),5.44(dd,1H),4.62(s,2H),4.01(q,1H),3.72~3.66(m,1H),2.77(dd,1H),2.62(dd,2H),2.44(dd,1H),2.41~2.35(m,1H),2.16~2.02(m,2H),1.67(q,1H),1.59~1.34(m,8H),1.06(q,1H),0.93(t,3H)
13C-NMR(CD
3OD):δ172.94,156.75,141.80,136.45,134.11,128.48,127.32,122.58,110.88,76.66,73.94,66.54,57.22,41.79,41.64,38.31,33.74,32.94,32.81,26.41,26.34,23.75,14.41
Example 36 and 37
Preparation treprostinil that
2-((1R, 2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-hydroxyl-1-((S)-3-hydroxyl octyl group)-1H-cyclopenta [b] naphthalene-5-base oxygen base) acetic acid
Example 36: you contain 2-((1R with 20%KOH (6ml) processing to prepare treprostinil by the product of example 33,2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-hydroxyl-1-((S)-3-hydroxyl octyl group)-1H-cyclopenta [b] naphthalene-5-base oxygen base) methyl alcohol (18ml) of acetonitrile (2g, 0.005mol) and refluxing 3 hours.Subsequently reactant is cooled to 10 ℃ and slowly add 3N HCl until pH=~ 8.Remove in a vacuum solvent.Add ethyl acetate and salt solution and slowly add 3N HCl until pH=2 subsequently.Use the ethyl acetate extraction reaction mixture.The acetic acid ethyl ester extract that merges is through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.By from ethanol/H
2Crystallization comes the purification of crude product among the O.Acquisition is the title compound of crystallized form.Productive rate: 81%.
Example 37: you at room temperature use potassium hydroxide (0.5g, 0.008mol) and 5%Pd/C (0.5g, 20 % by weight) processing to contain 2-((1R under hydrogen successively to prepare treprostinil by the product of example 34 and 35,2R, 3aS, 9aS)-2,3,3a, 4,9,9a-, six hydrogen-2-hydroxyl-1-((S, E)-3-hydroxyl suffering-1-thiazolinyl)-1H-cyclopenta [b] naphthalene-5-base oxygen base) acetic acid (2.5g, 0.008mol) anhydrous methanol (25ml) whole night.Filter reaction mixture with Celite pad subsequently.Vaporising under vacuum goes out solvent.With 50ml ethyl acetate and 50ml saturated sodium bicarbonate aqueous solution dilution resistates.Mixture is separated and with 50ml saturated sodium bicarbonate aqueous solution extraction organic layer.Combining water layer and slowly add 3N HCl subsequently until pH=~ 2.With 100ml ethyl acetate extraction water layer.Merge organic layer and through anhydrous magnesium sulfate drying.Leach solid.Vaporising under vacuum goes out solvent.Come the purification of crude product by crystallization.Acquisition is the title compound of crystallized form.Productive rate: 88%.
1H-NMR(CDCl
3):δ.7.08(t,1H),6.83(d,1H),6.69(d,1H),4.65(s,2H),3.75(q,1H),3.67~3.58(m,1H),2.82~2.73(m,2H),2.62~2.58(m,1H),2.51~2.47(m,1H),2.29~2.27(m,1H),2.20~2.15(m,1H),1.91~1.84(m,1H),1.66~1.65(m,1H),1.49~1.33(m,4H),1.32~1.21(m,8H),1.17(q,1H),0.91(t,3H)
13C-NMR(CDCl3):δ170.86,154.80,141.12,127.92,126.32,122.18,110.25,76.75,72.75,65.96,52.28,41.51,41.39,37.47,35.02,33.60,32.98,31.94,28.69,26.06,25.35,22.61,13.94。
Claims (25)
1. the method for preparation formula 1 compound,
P wherein
1Protecting group for phenolic group; P
2And P
3Protecting group for hydroxyl;
Be singly-bound or two key; R
2Be singly-bound or C
1-4Alkylidene group or-CH
2O-; And R
3Be C
1-7Alkyl or aryl or aralkyl, it is unsubstituted or separately through C
1-4Alkyl, halogen or trihalogenmethyl replace,
Described method comprises following steps:
(1) make the formula III compound:
P wherein
1And P
2As hereinbefore defined; With the cuprate reaction derived from the compound of formula II-1, formula II-2 or formula II-3,
Wherein X is halogen, R
4Be low alkyl group, and P
3,
R
2And R
3As hereinbefore defined; Form formula 1 compound.
2. method according to claim 1, wherein P
1Be alkyl, the allyl group that is unsubstituted, the benzyl that is unsubstituted or is substituted, ethanoyl, alkyl-carbonyl, methoxymethyl, methoxyl group thiomethyl, 2-methoxy ethoxy methyl, two (2-chloroethoxy) methyl, THP trtrahydropyranyl, tetrahydro thiapyran base, 4-methoxyl group THP trtrahydropyranyl, 4-methoxyl group tetrahydro thiapyran base, tetrahydrofuran base, tetrahydrochysene thio-furan base, 1-ethoxyethyl group, 1-methyl isophthalic acid-methoxy ethyl, trityl group or SiR
aR
bR
c, R wherein
a, R
bAnd R
cBe C independently of one another
1-8Alkyl, phenyl, benzyl, the phenyl that is substituted or the benzyl that is substituted.
3. method according to claim 1, wherein P
1Benzyl, ethanoyl, alkyl-carbonyl and the SiR that is selected from allyl group, is unsubstituted or is substituted
aR
bR
c, R wherein
a, R
bAnd R
cBe C independently of one another
1-8Alkyl, phenyl, benzyl, the phenyl that is substituted or the benzyl that is substituted.
4. method according to claim 1, wherein R
2Be singly-bound and R
3Be amyl group.
5. the method for preparation formula 6 compounds,
P wherein
2, P
3, R
2And R
3As defined in claim 1,
Described method comprises following steps:
(1) makes the formula III compound
P wherein
1And P
2As defined in claim 1; With the cuprate reaction derived from the compound of formula II-1, formula II-2 or formula II-3,
Wherein X,
R
2, R
3And R
4And P
3As defined in claim 1; Form formula 1 compound;
(2) make the ketone group of formula 1 compound carry out methylenation, form the methylene compound of formula 2;
(3) make described formula 2 compounds carry out hydroboration with borane reagent, then carry out oxidation with alkaline hydrogen peroxide, obtain the alkylol cpd of formula 3,
(4) make described formula 3 compounds in the presence of alkali, carry out sulfonylation with the alkylsulfonyl donor, form formula 4 compounds,
X wherein
1Be alkylsulfonyl;
(5) remove described P
1Group forms formula 5 compounds
X wherein
1Be alkylsulfonyl; With
(6) make described formula 5 compounds carry out alkylation in the molecule, form formula 6 compounds.
6. method according to claim 5, wherein said methylenation reagent is by CH
2Br
2, Zn and TiCl
4Preparation.
7. method according to claim 5, wherein said methylenation comprises the negatively charged ion that makes described formula 1 cyclopentanone and aminomethyl phenyl-N-methyl-sulfoximine and reacts in being fit to solvent, then in the solvent mixture of water-acetic acid-tetrahydrofuran (THF), process the thick adducts of gained with aluminium amalgam (aluminium amalgam), obtain described formula 2 compounds.
8. method according to claim 5, wherein said borane reagent is 9-boron dicyclo [3,3,1] nonane (9-BBN).
9. method according to claim 5, wherein said X
1Alkylsulfonyl be methane sulfonyl or p-toluenesulfonyl.
10. method according to claim 5, wherein R
2Be singly-bound and R
3Be amyl group.
11. the method for a preparation formula 6c compound,
P wherein
2, P
3, R
2And R
3As defined in claim 1,
Described method comprises following steps:
(1) makes the formula III compound
P wherein
1And P
2As defined in claim 1; With the cuprate reaction derived from the compound of formula II-1a, formula II-2 or formula II-3,
Wherein X, R
2, R
3, R
4And P
3As defined in claim 1; Form formula 1c compound;
(2) make the ketone group of described formula 1c compound carry out methylenation with methylenation reagent, form the methylene compound of formula 2c;
(3) make described formula 2c compound carry out hydroboration with borane reagent, then carry out oxidation with alkaline hydrogen peroxide, obtain the alkylol cpd of formula 3c
(4) make described formula 3c compound in the presence of alkali, carry out sulfonylation with the alkylsulfonyl donor, form formula 4c compound:
X wherein
1Be alkylsulfonyl;
(5) remove described P
1Group and with the two key hydrogenations in the ω side chain forms formula 5c compound
(6) make described formula 5c compound carry out alkylation in the molecule, form formula 6c compound.
12. method according to claim 11, wherein said methylenation reagent is by CH
2Br
2, Zn and TiCl
4Preparation.
13. method according to claim 11, wherein said methylenation comprises the negatively charged ion that makes described formula 1c cyclopentanone and aminomethyl phenyl-N-methyl-sulfoximine and reacts in being fit to solvent, then in the solvent mixture of water-acetic acid-tetrahydrofuran (THF), process the thick adducts of gained with aluminium amalgam, thereby obtain described formula 2c compound.
14. method according to claim 11, wherein said borane reagent are 9-boron dicyclo [3,3,1] nonane (9-BBN).
15. method according to claim 11, wherein said alkylsulfonyl are methane sulfonyl or p-toluenesulfonyl.
16. method according to claim 11, wherein R
2Be singly-bound and R
3Be amyl group.
17. a method for preparing treprostinil you (Treprostinil), it comprises following steps:
(1) makes formula III a compound
P wherein
1And P
2As defined in claim 1; With the cuprate reaction derived from the compound of formula II-1a, formula II-2a or formula II-3a,
Wherein X, R
4And P
3As defined in claim 1; Form formula 1d compound
(2) make the ketone group of described formula 1d compound carry out methylenation, form the methylene compound of formula 2d;
(3) make described formula 2d compound carry out hydroboration with borane reagent, then carry out oxidation with alkaline hydrogen peroxide, obtain the alkylol cpd of formula 3d
(4) make described formula 3d compound in the presence of alkali, carry out sulfonylation with the alkylsulfonyl donor, form formula 4d compound
X wherein
1Be alkylsulfonyl;
(5) remove described P
1Group forms formula 5d compound
(6) make described formula 5d compound carry out alkylation in the molecule, form formula 6d compound
(7) remove described P
2And P
3Group forms formula 7d compound
(8) make two key hydrogenations in the ω side chain of formula 7d compound, form formula 8d compound
(9) be halogen with X wherein; R
5Alkylating agent XCH for alkyl
2CN or XCH
2COOR
5Make phenolic group carry out alkylation, form formula 9d compound
Wherein Z be-CN or-COOR
5With
(10) with basic hydrolysis described formula 9d compound-CN or-COOR
5Group forms the treprostinil that.
18. method according to claim 17, wherein P
1Benzyl, ethanoyl, alkyl-carbonyl and the SiR that is selected from allyl group, is unsubstituted or is substituted
aR
bR
c, R wherein
a, R
bAnd R
cBe C independently of one another
1-8Alkyl, phenyl, benzyl, the phenyl that is substituted or the benzyl that is substituted.
19. method according to claim 17, step (1) ~ (6) form formula 6d compound, subsequently
(7) be halogen with X wherein, for example Cl, Br or I; R
5Alkylating agent XCH for alkyl
2CN or XCH
2COOR
5Make phenolic group carry out alkylation, form formula 7D compound
Wherein Z be-CN or-COOR
5With
(8) remove described P
2And P
3Group forms formula 8D compound
(9) with basic hydrolysis described formula 8D compound-CN or-COOR
5Group forms formula 9D
(10) make the two keys in the ω side chain of described formula 9D compound carry out hydrogenation, form treprostinil you.
20. one kind prepares your method of treprostinil, it comprises following steps:
(1) makes formula III a compound
P wherein
1Be benzyl and the P that is unsubstituted or is substituted
2As defined in claim 1; React with the cuprate derived from formula II-1b compound:
Wherein X, R
2, R
3, R
4And P
3As defined in claim 1; Form formula 1b compound
(2) make the ketone group of described formula 1b compound carry out methylenation, form the methylene compound of formula 2b;
(3) make described formula 2b compound carry out hydroboration with borane reagent, then carry out oxidation with alkaline hydrogen peroxide, obtain the alkylol cpd of formula 3b
(4) make formula 3b compound in the presence of alkali, carry out sulfonylation with the alkylsulfonyl donor, form formula 4b compound
X wherein
1Be alkylsulfonyl;
(5) remove described P
1Group forms formula 5b compound,
(6) make described formula 5b compound carry out alkylation in the molecule, form formula 6b compound
(7) remove described P
2And P
3Group forms formula 8d compound
(8) be halogen with X wherein; R
5Alkylating agent XCH for alkyl
2CN or XCH
2COOR
5Make phenolic group carry out alkylation, form formula 9d compound
Wherein Z be-CN or-COOR
5With
(9) with basic hydrolysis described formula 9d compound-CN or-COOR
5Group forms the treprostinil that.
21. the method for a preparation formula 8d compound,
It comprises following steps:
(1) makes the esterification of formula 6d compound
P wherein
2And P
3As defined in claim 1; Form the ester cpds of formula 10d
Wherein M is low alkyl group or the phenyl that is unsubstituted or is substituted;
(2) remove described P
2And P
3Group forms formula 11d compound
(3) make the two keys in the ω side chain of described formula 11d compound carry out hydrogenation and make subsequently the compound of hydrogenation carry out deacylation; Or make described formula 11d compound carry out deacylation and subsequently will be two keys in the ω side chain of the compound of deacylation carry out hydrogenation, form formula 8d compound.
22. method according to claim 21, wherein M is phenyl or 4-phenyl.
23. a formula 1e compound,
P wherein
1Be the benzyl that is unsubstituted or is substituted;
Be singly-bound or two key; R
2Be singly-bound or C
1-4Alkylidene group or-CH
2O-; R
3Be C
1-7Alkyl or aryl or aralkyl, it is unsubstituted or separately through C
1-4Alkyl, halogen or trihalogenmethyl replace; P
2' and P
3' be respectively the P such as the protecting group that is defined as hydroxyl in the claim 1
2And P
3Or be H independently.
24. a formula 8D-1 compound,
25. a formula 11-1 compound,
Wherein M is methyl, phenyl or 4-phenyl; And
Be singly-bound or two key.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13/216,378 US8524939B2 (en) | 2011-08-24 | 2011-08-24 | Intermediates for the synthesis of benzindene prostaglandins and preparations thereof |
| US13/216,378 | 2011-08-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102952157A true CN102952157A (en) | 2013-03-06 |
| CN102952157B CN102952157B (en) | 2016-04-13 |
Family
ID=46982410
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210305379.8A Active CN102952157B (en) | 2011-08-24 | 2012-08-24 | For the synthesis of intermediate and its preparation of benzindene prostaglandin(PG) |
Country Status (6)
| Country | Link |
|---|---|
| US (2) | US8524939B2 (en) |
| EP (1) | EP2581361B1 (en) |
| JP (2) | JP5654532B2 (en) |
| KR (2) | KR101551769B1 (en) |
| CN (1) | CN102952157B (en) |
| TW (2) | TWI518060B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103193627A (en) * | 2012-01-10 | 2013-07-10 | 上海天伟生物制药有限公司 | Crystal form, preparation method and application of prostaglandin analogue |
| CN103193626A (en) * | 2012-01-10 | 2013-07-10 | 上海天伟生物制药有限公司 | Crystal form, preparation method and application of prostaglandin analogue |
| CN105061391A (en) * | 2015-08-26 | 2015-11-18 | 杨雪峰 | Method for synthesizing arylenealkyne-substituted heterocycle ketone compound |
| CN105164098A (en) * | 2013-03-14 | 2015-12-16 | 联合治疗公司 | Solid forms of treprostinil |
| CN107001221A (en) * | 2014-10-08 | 2017-08-01 | 奇诺因药物和化学工厂私人有限公司 | Method for preparing treprostinil that |
| CN109400543A (en) * | 2017-08-15 | 2019-03-01 | 暨南国际大学 | Triazine precursor, method for preparing triazine precursor and application of triazine precursor |
| CN109762012A (en) * | 2017-11-10 | 2019-05-17 | 佳和桂科技股份有限公司 | The preparation method of cyclopentano [B] naphthol derivative and wherein mesosome |
| CN113620840A (en) * | 2020-05-07 | 2021-11-09 | 佳和桂科技股份有限公司 | Crystals of an intermediate for benzindene prostaglandins and methods of making the same |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110590547A (en) | 2012-12-07 | 2019-12-20 | 开曼化学股份有限公司 | Method for synthesizing prostacyclin derivative |
| US9505737B2 (en) | 2013-01-11 | 2016-11-29 | Corsair Pharma, Inc. | Treprostinil derivative compounds and methods of using same |
| WO2014110491A1 (en) | 2013-01-11 | 2014-07-17 | Theratrophix Llc | Prodrugs of treprostinil |
| US9469600B2 (en) | 2013-10-25 | 2016-10-18 | Insmed Incorporated | Prostacyclin compounds, compositions and methods of use thereof |
| WO2016081658A1 (en) | 2014-11-18 | 2016-05-26 | Insmed Incorporated | Methods of manufacturing treprostinil and treprostinil derivative prodrugs |
| CA2967899C (en) | 2014-12-03 | 2023-09-19 | Steadymed Ltd | Preservative-free treprostinil formulations and methods and devices for use with same |
| US9394227B1 (en) | 2015-06-17 | 2016-07-19 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| US9643911B2 (en) | 2015-06-17 | 2017-05-09 | Corsair Pharma, Inc. | Treprostinil derivatives and compositions and uses thereof |
| KR101830693B1 (en) | 2016-04-28 | 2018-02-21 | 연성정밀화학(주) | Process for Preparing Treprostinil and Intermediate Therefor |
| BR112021021775A2 (en) | 2019-04-29 | 2022-01-04 | Insmed Inc | Dry powder compositions of treprostinil prodrugs and methods of use thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003070163A2 (en) * | 2002-01-16 | 2003-08-28 | United Therapeutics Corporation | Prostacyclin derivatives for treating cancer |
| CN101003504A (en) * | 2006-01-18 | 2007-07-25 | 佳和桂科技股份有限公司 | Processes and intermediates for the preparations of prostaglandins |
| CN101891715A (en) * | 2009-05-22 | 2010-11-24 | 上海天伟生物制药有限公司 | Novel compound and preparation method and use thereof |
| CN101903324A (en) * | 2007-12-17 | 2010-12-01 | 联合治疗公司 | A kind of modification method for preparing the activeconstituents Qu Qianlie element among the Remodulin |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4233231A (en) | 1977-11-22 | 1980-11-11 | American Cyanamid Company | Novel vinyl-stannyl derivatives |
| US4306075A (en) * | 1980-03-28 | 1981-12-15 | The Upjohn Company | Composition and process |
| JPS57171965A (en) * | 1981-04-15 | 1982-10-22 | Teijin Ltd | Novel prostaglandin intermediate and its preparation |
| US4415501A (en) | 1981-12-16 | 1983-11-15 | American Cyanamid Company | Alkenylzirconium reagents useful for prostaglandin analog synthesis |
| JPS6187638A (en) * | 1984-10-08 | 1986-05-06 | Teijin Ltd | Preparation of 2,3-disubstituted-4-substituted cyclopentanone |
| JPH0794400B2 (en) * | 1993-07-19 | 1995-10-11 | 日本ゼオン株式会社 | Method for producing steroid intermediate |
| CA2307163C (en) * | 1997-10-24 | 2014-05-06 | United Therapeutics Corporation | Process for stereoselective synthesis of prostacyclin derivatives |
| US6294679B1 (en) | 1999-04-12 | 2001-09-25 | Chirotech Technology Limited | Intermediate for the synthesis of prostaglandins |
| US6700025B2 (en) * | 2001-01-05 | 2004-03-02 | United Therapeutics Corporation | Process for stereoselective synthesis of prostacyclin derivatives |
| EP1810967B1 (en) * | 2006-01-18 | 2014-07-30 | Chirogate International Inc. | Processes and intermediates for the preparations of prostaglandins |
| TWI310763B (en) * | 2006-01-18 | 2009-06-11 | Chirogate Int Inc | Processes and intermediates for the preparations of prostaglandins |
| WO2010109476A2 (en) * | 2009-01-19 | 2010-09-30 | Matrix Laboratories Ltd | Improved process for the preparation of prostaglandins and analogues thereof |
| CN101891596B (en) * | 2009-05-22 | 2013-12-11 | 上海天伟生物制药有限公司 | New compound and preparation method and application thereof |
| CA2710726C (en) * | 2010-07-22 | 2016-02-23 | Alphora Research Inc. | Synthesis of treprostinil and intermediates useful therein |
-
2011
- 2011-08-24 US US13/216,378 patent/US8524939B2/en active Active
-
2012
- 2012-08-16 JP JP2012180637A patent/JP5654532B2/en active Active
- 2012-08-22 TW TW103117519A patent/TWI518060B/en active
- 2012-08-22 TW TW101130514A patent/TWI454453B/en active
- 2012-08-23 EP EP12181574.0A patent/EP2581361B1/en active Active
- 2012-08-24 KR KR1020120093181A patent/KR101551769B1/en active IP Right Grant
- 2012-08-24 CN CN201210305379.8A patent/CN102952157B/en active Active
-
2013
- 2013-07-30 US US13/954,191 patent/US8658837B2/en active Active
-
2014
- 2014-11-20 JP JP2014235220A patent/JP6054935B2/en active Active
-
2015
- 2015-06-01 KR KR1020150077178A patent/KR101658855B1/en active IP Right Grant
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003070163A2 (en) * | 2002-01-16 | 2003-08-28 | United Therapeutics Corporation | Prostacyclin derivatives for treating cancer |
| US20030166728A1 (en) * | 2002-01-16 | 2003-09-04 | Robert Shorr | Prostacyclin derivative containing compositions and methods of using the same for the treatment of cancer |
| CN101003504A (en) * | 2006-01-18 | 2007-07-25 | 佳和桂科技股份有限公司 | Processes and intermediates for the preparations of prostaglandins |
| CN101903324A (en) * | 2007-12-17 | 2010-12-01 | 联合治疗公司 | A kind of modification method for preparing the activeconstituents Qu Qianlie element among the Remodulin |
| CN101891715A (en) * | 2009-05-22 | 2010-11-24 | 上海天伟生物制药有限公司 | Novel compound and preparation method and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| PAUL A等，: "SYNTHESIS OF BENZINDENE PROSTAGLANDINS: A NOVEL POTENT CLASS OF STABLE PRGSTACYCLIN ANALOGS", 《TETRAHEDRON LETTERS》 * |
| ROBERT M. MORIARTY等，: "The Intramolecular Asymmetric Pauson-Khand Cyclization as a Novel and General Stereoselective Route to Benzindene Prostacyclins: Synthesis of UT-15 (Treprostinil)", 《J. ORG. CHEM.》 * |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103193627B (en) * | 2012-01-10 | 2016-04-20 | 上海天伟生物制药有限公司 | Crystal formation of a kind of prostaglandin analogue and its production and use |
| CN103193626A (en) * | 2012-01-10 | 2013-07-10 | 上海天伟生物制药有限公司 | Crystal form, preparation method and application of prostaglandin analogue |
| CN103193627A (en) * | 2012-01-10 | 2013-07-10 | 上海天伟生物制药有限公司 | Crystal form, preparation method and application of prostaglandin analogue |
| CN105164098A (en) * | 2013-03-14 | 2015-12-16 | 联合治疗公司 | Solid forms of treprostinil |
| CN107001221B (en) * | 2014-10-08 | 2021-05-25 | 奇诺因药物和化学工厂私人有限公司 | Method for preparing treprostinil |
| CN107001221A (en) * | 2014-10-08 | 2017-08-01 | 奇诺因药物和化学工厂私人有限公司 | Method for preparing treprostinil that |
| CN113292419A (en) * | 2014-10-08 | 2021-08-24 | 奇诺因药物和化学工厂私人有限公司 | Method for preparing treprostinil |
| CN105061391B (en) * | 2015-08-26 | 2017-09-01 | 潍坊医学院 | A kind of synthetic method of sweet-smelling alkynyl substituted heterocycle ketone compounds |
| CN105061391A (en) * | 2015-08-26 | 2015-11-18 | 杨雪峰 | Method for synthesizing arylenealkyne-substituted heterocycle ketone compound |
| CN109400543A (en) * | 2017-08-15 | 2019-03-01 | 暨南国际大学 | Triazine precursor, method for preparing triazine precursor and application of triazine precursor |
| US11299504B2 (en) | 2017-08-15 | 2022-04-12 | National Chi Nan University | Process for preparing a triazine-based precursor, the precursor prepared thereby, a method for producing a micro-particulate complex using the precursor, and the micro-particulate complex produced thereby |
| CN109762012A (en) * | 2017-11-10 | 2019-05-17 | 佳和桂科技股份有限公司 | The preparation method of cyclopentano [B] naphthol derivative and wherein mesosome |
| CN109762012B (en) * | 2017-11-10 | 2021-08-13 | 佳和桂科技股份有限公司 | Process for producing cyclopenta [ B ] naphthol derivative and intermediate therefor |
| CN113620840A (en) * | 2020-05-07 | 2021-11-09 | 佳和桂科技股份有限公司 | Crystals of an intermediate for benzindene prostaglandins and methods of making the same |
Also Published As
| Publication number | Publication date |
|---|---|
| TWI518060B (en) | 2016-01-21 |
| TW201323391A (en) | 2013-06-16 |
| EP2581361A1 (en) | 2013-04-17 |
| KR20130022389A (en) | 2013-03-06 |
| CN102952157B (en) | 2016-04-13 |
| JP6054935B2 (en) | 2016-12-27 |
| JP2015083570A (en) | 2015-04-30 |
| US20130317245A1 (en) | 2013-11-28 |
| JP5654532B2 (en) | 2015-01-14 |
| JP2013047224A (en) | 2013-03-07 |
| US8524939B2 (en) | 2013-09-03 |
| KR101551769B1 (en) | 2015-09-09 |
| US8658837B2 (en) | 2014-02-25 |
| EP2581361B1 (en) | 2018-06-06 |
| US20130053581A1 (en) | 2013-02-28 |
| KR20150067112A (en) | 2015-06-17 |
| TW201433565A (en) | 2014-09-01 |
| TWI454453B (en) | 2014-10-01 |
| KR101658855B1 (en) | 2016-09-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102952157B (en) | For the synthesis of intermediate and its preparation of benzindene prostaglandin(PG) | |
| TWI465458B (en) | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives | |
| JP4806351B2 (en) | Method for producing stilbene derivatives | |
| CN101624390B (en) | Preparation method of key intermediate of rosuvastatin calcium side chain | |
| CN104370755A (en) | Preparation method for optical activity active 3-amino butanol and optical activity 3-amino butyric acid | |
| CN101003504A (en) | Processes and intermediates for the preparations of prostaglandins | |
| EP2048139A1 (en) | PROCESS FOR PRODUCTION OF (±)-3a,6,6,9a TETRAMETHYLDECAHYDRONAPHTHO[2,1-b]FURAN-2(1H)-ONE | |
| CN110713477B (en) | Preparation method of LUBIPROSTONE (LUBIPROSTONE) and intermediate thereof | |
| CN115108904A (en) | Synthesis method of betimeric acid bulk drug | |
| CN101891716B (en) | Synthesis method of S-beta-hydroxy-gamma-butyrolactone | |
| CN103159704B (en) | Cabazitaxel intermediates and cabazitaxel intermediate preparation method | |
| KR100763770B1 (en) | Process for preparing chiral intermediates useful in synthesis of atorvastatin | |
| JPH1017561A (en) | Allylalcohol compounds and their production | |
| CN1129567C (en) | Process for preparation of cyclopropylacetylene derivatives | |
| WO2013168780A1 (en) | Method for producing optically active 2-vinylcyclopropane-1,1-dicarboxylic acid ester | |
| Walkup et al. | Preparation of 2-(Tetrahydrofuran-2′-YL)-l, 4-Pentadienes From γ-Allenyl Alcohols via Oxymercuration Followed by Palladium (II)-Medlated all Ylation | |
| JP2002173472A (en) | Method for producing optically active 1-(trifluoromethyl mono-substituted phenyl) ethylamine | |
| WO2013137330A1 (en) | Method for producing optically active 2-vinylcyclopropane-1,1-dicarboxylic acid ester | |
| CN105566150A (en) | Preparation method of aliskiren | |
| CN104418707A (en) | Natural product fructus psoraleae phenol and asymmetric synthesis method of enantiomer thereof | |
| US20040249220A1 (en) | Process for producing optically active 2-alkoxy-1-(trifluoromethyl-substituted phenyl) ethanol derivatives | |
| US7390926B2 (en) | Process for the diastereoselective alkylation of an ether oxime of the compound nopinone and novel intermediates for the synthesis of diastereospecific 2-amino-nopinone derivatives substituted on carbon 3 | |
| CN103613607A (en) | Method for synthesizing multi-substituted silicon-based allene in highly selective way | |
| JP5623099B2 (en) | Method for producing N-oxycarbonyl- (2S) -oxycarbonyl- (5S) -phosphonylpyrrolidine derivative | |
| CN118027091A (en) | Preparation method of treprostinil and intermediate thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |